Sample records for n-acetylaspartate naa choline

  1. 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

  2. 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.

  3. 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.

  4. 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

  5. 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.

  6. 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.

  7. 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.

  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. 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

  10. 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.

  11. 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.

  12. 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.

  13. N-acetylaspartate (NAA) induces neuronal differentiation of SH-SY5Y neuroblastoma cell line and sensitizes it to chemotherapeutic agents

    PubMed Central

    Mazzoccoli, Carmela; Ruggieri, Vitalba; Tataranni, Tiziana; Agriesti, Francesca; Laurenzana, Ilaria; Fratello, Angelo; Capitanio, Nazzareno; Piccoli, Claudia

    2016-01-01

    Neuroblastoma is the most commonly extra-cranial solid tumor of childhood frequently diagnosed. The nervous system-specific metabolite N-acetylaspartate (NAA) is synthesized from aspartate and acetyl-CoA in neurons, it is among the most abundant metabolites present in the central nervous system (CNS) and appears to be involved in many CNS disorders. The functional significance of the high NAA concentration in the brain remains uncertain, but it confers to NAA a unique clinical significance exploited in magnetic resonance spectroscopy. In the current study, we show that treatment of SH-SY5Y neuroblastoma-derived cell line with sub-cytotoxic physiological concentrations of NAA inhibits cell growth. This effect is partly due to enhanced apoptosis, shown by decrease of the anti-apoptotic factors survivin and Bcl-xL, and partly to arrest of the cell-cycle progression, linked to enhanced expression of the cyclin-inhibitors p53, p21Cip1/Waf1 and p27Kip1. Moreover, NAA-treated SH-SY5Y cells exhibited morphological changes accompanied with increase of the neurogenic markers TH and MAP2 and down-regulation of the pluripotency markers OCT4 and CXCR4/CD184. Finally, NAA-pre-treated SH-SY5Y cells resulted more sensitive to the cytotoxic effect of the chemotherapeutic drugs Cisplatin and 5-fluorouracil. To our knowledge, this is the first study demonstrating the neuronal differentiating effects of NAA in neuroblastoma cells. NAA may be a potential preconditioning or adjuvant compound in chemotherapeutic treatment. PMID:27036033

  14. N-acetylaspartate (NAA) induces neuronal differentiation of SH-SY5Y neuroblastoma cell line and sensitizes it to chemotherapeutic agents.

    PubMed

    Mazzoccoli, Carmela; Ruggieri, Vitalba; Tataranni, Tiziana; Agriesti, Francesca; Laurenzana, Ilaria; Fratello, Angelo; Capitanio, Nazzareno; Piccoli, Claudia

    2016-05-03

    Neuroblastoma is the most commonly extra-cranial solid tumor of childhood frequently diagnosed. The nervous system-specific metabolite N-acetylaspartate (NAA) is synthesized from aspartate and acetyl-CoA in neurons, it is among the most abundant metabolites present in the central nervous system (CNS) and appears to be involved in many CNS disorders. The functional significance of the high NAA concentration in the brain remains uncertain, but it confers to NAA a unique clinical significance exploited in magnetic resonance spectroscopy. In the current study, we show that treatment of SH-SY5Y neuroblastoma-derived cell line with sub-cytotoxic physiological concentrations of NAA inhibits cell growth. This effect is partly due to enhanced apoptosis, shown by decrease of the anti-apoptotic factors survivin and Bcl-xL, and partly to arrest of the cell-cycle progression, linked to enhanced expression of the cyclin-inhibitors p53, p21Cip1/Waf1 and p27Kip1. Moreover, NAA-treated SH-SY5Y cells exhibited morphological changes accompanied with increase of the neurogenic markers TH and MAP2 and down-regulation of the pluripotency markers OCT4 and CXCR4/CD184. Finally, NAA-pre-treated SH-SY5Y cells resulted more sensitive to the cytotoxic effect of the chemotherapeutic drugs Cisplatin and 5-fluorouracil.To our knowledge, this is the first study demonstrating the neuronal differentiating effects of NAA in neuroblastoma cells. NAA may be a potential preconditioning or adjuvant compound in chemotherapeutic treatment.

  15. 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.

  16. 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

  17. N-acetylaspartate (NAA) correlates inversely with cannabis use in a frontal language processing region of neocortex in MDMA (Ecstasy) polydrug users: a 3 T magnetic resonance spectroscopy study.

    PubMed

    Cowan, Ronald L; Joers, James M; Dietrich, Mary S

    2009-03-01

    Impaired verbal memory is common in MDMA (Ecstasy) polydrug users. The contributions of Ecstasy or polydrug exposure to reduced verbal memory are unclear, as is the neural basis for this cognitive deficit. Ecstasy users have reduced gray matter in brain regions mediating verbal memory (BA 18, 21 and 45). N-acetylaspartate (NAA) as a neuronal marker and myoinositol (mI) as a glial marker are inconsistently affected in Ecstasy users. We used 3 T MRS in 17 recreational drug users to test the hypothesis that Ecstasy polydrug use would be associated with altered NAA or mI in BA 18, 21 and 45. No effects were seen for mI. Metabolite ratios for NAA (mean+/-SD) were: BA 18-NAA/Cr (2.030+/-0.188); BA 21-NAA/Cr (1.861+/-0.325); BA 45-NAA/Cr (1.925+/-0.329). Lifetime cannabis use was significantly associated with BA 45 NAA/Cr (r=-0.687, p=0.014) but not with NAA in BA 18 or 21. In contrast, there were no statistically significant associations for lifetime use of Ecstasy, alcohol, or cocaine with NAA. These findings suggest that cannabis use may contribute to altered neuronal integrity in Ecstasy polydrug users in a brain region associated with verbal memory processing.

  18. 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

  19. N-acetylaspartate (NAA) correlates inversely with cannabis use in a frontal language processing region of neocortex in MDMA (Ecstasy) Polydrug Users: a 3 Tesla Magnetic Resonance Spectroscopy Study

    PubMed Central

    Cowan, Ronald L; Joers, James M; Dietrich, Mary S

    2015-01-01

    Impaired verbal memory is common in MDMA (Ecstasy) polydrug users. The contributions of Ecstasy or polydrug exposure to reduced verbal memory are unclear, as is the neural basis for this cognitive deficit. Ecstasy users have reduced gray matter in brain regions mediating verbal memory (BA 18, 21 and 45). N-acetylaspartate (NAA) as a neuronal marker and myoinositol (mI) as a glial marker are inconsistently affected in Ecstasy users. We used 3 Tesla MRS in 17 recreational drug users to test the hypothesis that Ecstasy polydrug use would be associated with altered NAA or mI in BA 18, 21 and 45. No effects were seen for mI. Metabolite ratios for NAA (mean ± SD) were: BA 18--NAA/Cr (2.030 ± 0.188); BA 21--NAA/Cr (1.861 ± 0.325); BA 45--NAA/Cr (1.925 ± 0.329). Lifetime cannabis use was significantly associated with BA 45 NAA/Cr (r = −0.687, p = 0.014) but not with NAA in BA 18 or 21. In contrast, there were no statistically significant associations for lifetime use of Ecstasy, alcohol, or cocaine with NAA. These findings suggest that cannabis use may contribute to altered neuronal integrity in Ecstasy polydrug users in a brain region associated with verbal memory processing. PMID:19032963

  20. 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.

  1. 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.

  2. 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

  3. 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

  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. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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

  10. 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.

  11. 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…

  12. 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

  13. 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

  14. 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.

  15. 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.

  16. Reduced NAA in motor and non-motor brain regions in amyotrophic lateral sclerosis: a cross-sectional and longitudinal study.

    PubMed

    Rule, R R; Suhy, J; Schuff, N; Gelinas, D F; Miller, R G; Weiner, M W

    2004-09-01

    After replication of previous findings we aimed to: 1) determine if previously reported (1)H MRSI differences between ALS patients and control subjects are limited to the motor cortex; and 2) determine the longitudinal metabolic changes corresponding to varying levels of diagnostic certainty. Twenty-one patients with possible/suspected ALS, 24 patients with probable/definite ALS and 17 control subjects underwent multislice (1)H MRSI co-registered with tissue-segmented MRI to obtain concentrations of the brain metabolites N-acetylaspartate (NAA), creatine, and choline in the left and right motor cortex and in gray matter and white matter of non-motor regions in the brain. In the more affected hemisphere, reductions in the ratios, NAA/Cho and NAA/Cre+Cho were observed both within (12.6% and 9.5% respectively) and outside (9.2% and 7.3% respectively) the motor cortex in probable/definite ALS. However, these reductions were significantly greater within the motor cortex (P<0.05 for NAA/Cho and P<0.005 for NAA/Cre+Cho). Longitudinal changes in NAA were observed at three months within the motor cortex of both possible/suspected ALS patients (P<0.005) and at nine months outside the motor cortex of probable/definite patients (P<0.005). However, there was no clear pattern of progressive change over time. NAA ratios are reduced in the motor cortex and outside the motor cortex in ALS, suggesting widespread neuronal injury. Longitudinal changes of NAA are not reliable, suggesting that NAA may not be a useful surrogate marker for treatment trials.

  17. 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

  18. 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

  19. 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.

  20. 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

  1. 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

  2. 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.

  3. 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

  4. 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.

  5. Low thalamic NAA-concentration corresponds to strong neural activation in working memory in Kleine-Levin syndrome.

    PubMed

    Vigren, Patrick; Tisell, Anders; Engström, Maria; Karlsson, Thomas; Leinhard Dahlqvist, Olof; Lundberg, Peter; Landtblom, Anne-Marie

    2013-01-01

    Kleine Levin Syndrome (KLS) is a rare disorder of periodic hypersomnia and behavioural disturbances in young individuals. It has previously been shown to be associated with disturbances of working memory (WM), which, in turn, was associated with higher activation of the thalamus with increasing WM load, demonstrated with functional magnetic resonance imaging (fMRI). In this study we aimed to further elucidate how these findings are related to the metabolism of the thalamus. fMRI and magnetic resonance spectroscopy were applied while performing a WM task. Standard metabolites were examined: n-acetylaspartate (NAA), myo-inositol, choline, creatine and glutamate-glutamine. Fourteen KLS-patients and 15 healthy controls participated in the study. The patients with active disease were examined in asymptomatic periods. There was a statistically significant negative correlation between thalamic fMRI-activation and thalamic NAA, i.e., high fMRI-activation corresponded to low NAA-levels. This correlation was not seen in healthy controls. Thalamic levels of NAA in patients and controls showed no significant differences between the groups. None of the other metabolites showed any co-variation with fMRI-activation. This study shows negative correlation between NAA-levels and fMRI-activity in the left thalamus of KLS-patients while performing a WM task. This correlation could not be found in healthy control subjects, primarily interpreted as an effect of increased effort in the patient group upon performing the task. It might indicate a disturbance in the neuronal networks responsible for WM in KLS patients, resulting in higher effort at lower WM load, compared with healthy subjects. The general relationship between NAA and BOLD-signal is also discussed in the article.

  6. Reduced hippocampal N-acetyl-aspartate (NAA) as a biomarker for overweight.

    PubMed

    Coplan, Jeremy D; Fathy, Hassan M; Abdallah, Chadi G; Ragab, Sherif A; Kral, John G; Mao, Xiangling; Shungu, Dikoma C; Mathew, Sanjay J

    2014-01-01

    We previously demonstrated an inverse relationship between both dentate gyrus neurogenesis - a form of neuroplasticity - and expression of the antiapoptotic gene marker, BCL-2 and adult macaque body weight. We therefore explored whether a similar inverse correlation existed in humans between body mass index (BMI) and hippocampal N-acetyl-aspartate (NAA), a marker of neuronal integrity and putatively, neuroplasticity. We also studied the relationship of a potentially neurotoxic process, worry, to hippocampal NAA in patients with generalized anxiety disorder (GAD) and control subjects (CS). We combined two previously studied cohorts of GAD and control subjects. Using proton magnetic resonance spectroscopy imaging ((1)H MRSI) in medication-free patients with GAD (n = 29) and a matched healthy control group (n = 22), we determined hippocampal concentrations of (1) NAA (2) choline containing compounds (CHO), and (3) Creatine + phosphocreatine (CR). Data were combined from 1.5 T and 3 T scans by converting values from each cohort to z-scores. Overweight and GAD diagnosis were used as categorical variables while the Penn State Worry Questionnaire (PSWQ) and Anxiety Sensitivity Index (ASI) were used as dependent variables. Overweight subjects (BMI ≥ 25) exhibited lower NAA levels in the hippocampus than normal-weight subjects (BMI < 25) (partial Eta-squared = 0.14) controlling for age, sex and psychiatric diagnosis, and the effect was significant for the right hippocampus in both GAD patients and control subjects. An inverse linear correlation was noted in all subjects between right hippocampal NAA and BMI. High scores on the PSWQ predicted low hippocampal NAA and CR. Both BMI and worry were independent inverse predictors of hippocampal NAA. Overweight was associated with reduced NAA concentrations in the hippocampus with a strong effect size. Future mechanistic studies are warranted.

  7. Reduced hippocampal N-acetyl-aspartate (NAA) as a biomarker for overweight☆

    PubMed Central

    Coplan, Jeremy D.; Fathy, Hassan M.; Abdallah, Chadi G.; Ragab, Sherif A.; Kral, John G.; Mao, Xiangling; Shungu, Dikoma C.; Mathew, Sanjay J.

    2014-01-01

    Objective We previously demonstrated an inverse relationship between both dentate gyrus neurogenesis – a form of neuroplasticity – and expression of the antiapoptotic gene marker, BCL-2 and adult macaque body weight. We therefore explored whether a similar inverse correlation existed in humans between body mass index (BMI) and hippocampal N-acetyl-aspartate (NAA), a marker of neuronal integrity and putatively, neuroplasticity. We also studied the relationship of a potentially neurotoxic process, worry, to hippocampal NAA in patients with generalized anxiety disorder (GAD) and control subjects (CS). Methods We combined two previously studied cohorts of GAD and control subjects. Using proton magnetic resonance spectroscopy imaging (1H MRSI) in medication-free patients with GAD (n = 29) and a matched healthy control group (n = 22), we determined hippocampal concentrations of (1) NAA (2) choline containing compounds (CHO), and (3) Creatine + phosphocreatine (CR). Data were combined from 1.5 T and 3 T scans by converting values from each cohort to z-scores. Overweight and GAD diagnosis were used as categorical variables while the Penn State Worry Questionnaire (PSWQ) and Anxiety Sensitivity Index (ASI) were used as dependent variables. Results Overweight subjects (BMI ≥ 25) exhibited lower NAA levels in the hippocampus than normal-weight subjects (BMI < 25) (partial Eta-squared = 0.14) controlling for age, sex and psychiatric diagnosis, and the effect was significant for the right hippocampus in both GAD patients and control subjects. An inverse linear correlation was noted in all subjects between right hippocampal NAA and BMI. High scores on the PSWQ predicted low hippocampal NAA and CR. Both BMI and worry were independent inverse predictors of hippocampal NAA. Conclusion Overweight was associated with reduced NAA concentrations in the hippocampus with a strong effect size. Future mechanistic studies are warranted. PMID:24501701

  8. 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

  9. N-Acetylaspartate Reduction in the Medial Prefrontal Cortex Following 8 weeks of Risperidone Treatment in First-Episode Drug-Naïve Schizophrenia Patients

    PubMed Central

    Zong, Xiaofen; Hu, Maolin; Li, Zongchang; Cao, Hongbao; He, Ying; Liao, Yanhui; Zhou, Jun; Sang, Deen; Zhao, Hongzeng; Tang, Jinsong; Lv, Luxian; Chen, Xiaogang

    2015-01-01

    It is unclear whether N-acetylaspartate (NAA) depletions documented in schizophrenia patients might be due to the disease progression or medications. Here we investigated longitudinal NAA changes in drug-naïve first-episode patients (FEP) who are relatively free from chronicity. Forty-two drug-naïve FEP and 38 controls were enrolled in this study to explore the effect of 8-week risperidone monotherapy on NAA. All spectra were obtained from the medial prefrontal cortex (MPFC) on a 3.0 T MRI and analyzed with LCModel. At baseline, patients presented no significant differences in NAA (P = 0.084) or NAA/Cr + Pcr (P = 0.500) compared to controls; NAA levels were negatively correlated with PANSS total scores (P = 0.001) and WCST-PE (P = 0.041). After treatment, patients demonstrated significant reductions of NAA (P < 0.001) and NAA/Cr + Pcr (P < 0.001), and significant improvement in PANSS-P (P < 0.001) and PANSS-G (P < 0.001) symptoms. We detected no significant correlations between NAA alterations and PANSS-P (P = 0.679) or PANSS-G (P = 0.668) symptom changes; nor did NAA/Cr + Pcr changes with alterations in PANSS-P (P = 0.677) and PANSS-G (P = 0.616). This is the first evidence that short-term risperidone treatment induces an acute reduction of MPFC NAA during the early phase of schizophrenia, which may be a previously unavailable biomarker to indicate risperidone with a similar pharmacological mechanism, although the functional significance is still unclear. PMID:25778460

  10. 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

  11. 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.

  12. A pilot study of hippocampal volume and N-acetylaspartate (NAA) as response biomarkers in riluzole-treated patients with GAD.

    PubMed

    Abdallah, Chadi G; Coplan, Jeremy D; Jackowski, Andrea; Sato, João R; Mao, Xiangling; Shungu, Dikoma C; Mathew, Sanjay J

    2013-04-01

    Anxiolytic benefit following chronic treatment with the glutamate modulating agent riluzole in patients with generalized anxiety disorder (GAD) was previously associated with differential changes in hippocampal NAA concentrations. Here, we investigated the association between hippocampal volume and hippocampal NAA in the context of riluzole response in GAD. Eighteen medication-free adult patients with GAD received 8-week of open-label riluzole. Ten healthy subjects served as a comparison group. Participants underwent magnetic resonance imaging and spectroscopy at baseline and at the end of Week 8. GAD patients who completed all interventions were classified as remitters (n=7) or non-remitters (n=6), based on final Hamilton Anxiety Rating Scale (HAM-A) scores ≤7. At baseline, GAD patients had a significant reduction in total hippocampal volume compared to healthy subjects (F(1,21)=6.55, p=0.02). This reduction was most pronounced in the remitters, compared to non-remitters and healthy subjects. Delta (final-baseline) hippocampal volume was positively correlated with delta NAA in GAD. This positive association was highly significant in the right hippocampus in GAD [r=0.81, p=0.002], with no significant association in healthy subjects [Fisher r-to-z p=0.017]. Across all GAD patients, delta hippocampal volume was positively associated with improvement in HAM-A (rspearman=0.62, p=0.03). These preliminary findings support hippocampal NAA and volume as neural biomarkers substantially associated with therapeutic response to a glutamatergic drug. Copyright © 2012 Elsevier B.V. and ECNP. All rights reserved.

  13. Changes in NAA and lactate following ischemic stroke: a serial MR spectroscopic imaging study.

    PubMed

    Muñoz Maniega, S; Cvoro, V; Chappell, F M; Armitage, P A; Marshall, I; Bastin, M E; Wardlaw, J M

    2008-12-09

    Although much tissue damage may occur within the first few hours of ischemic stroke, the duration of tissue injury is not well defined. We assessed the temporal pattern of neuronal loss and ischemia after ischemic stroke using magnetic resonance spectroscopic imaging (MRSI) and diffusion-weighted imaging (DWI). We measured N-acetylaspartate (NAA) and lactate in 51 patients with acute ischemic stroke at five time points, from admission to 3 months, in voxels classified as normal, possibly or definitely abnormal (ischemic) according to the appearance of the stroke lesion on the admission DWI. We compared changes in NAA and lactate in different voxel classes using linear mixed models. NAA was significantly reduced from admission in definitely and possibly abnormal (p < 0.01) compared to contralateral normal voxels, reaching a nadir by 2 weeks and remaining reduced at 3 months. Lactate was significantly increased in definitely and possibly abnormal voxels (p < 0.01) during the first 5 days, falling to normal at 2 weeks, rising again later in these voxels. The progressive fall in N-acetylaspartate suggests that some additional neuronal death may continue beyond the first few hours for up to 2 weeks or longer. The mechanism is unclear but, if correct, then it is possible that interventions to limit this ongoing subacute tissue damage might add to the benefit of hyperacute treatment, making further improvements in outcome possible.

  14. 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.

  15. 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

  16. MRS of pilocytic astrocytoma: The peak at 2 ppm may not be NAA.

    PubMed

    Tamrazi, Benita; Nelson, Marvin D; Blüml, Stefan

    2017-08-01

    To determine whether the chemical shift of residual N-acetylaspartate (NAA) signal in pilocytic astrocytomas (PA) is consistent with the position of the NAA peak in controls. MR spectra from 27 pediatric World Health Organization (WHO) grade I pilocytic astrocytoma patients, fifteen patients with WHO grade II and high-grade (III-IV) astrocytomas, and 36 controls were analyzed. All spectra were acquired with a short echo time (35 ms), single voxel point-resolved spectroscopy sequence on clinical 3 tesla scanners. Fully automated LCModel software was used for processing, which included the fitting of peak positions for NAA and creatine (Cr). The chemical shift difference between the NAA and Cr peaks was significantly smaller (by 0.016 ± 0.005 parts per million, P < 1e-10) in PAs than in controls and was also smaller than what was observed in infiltrative astrocytomas. The chemical shift position of the residual NAA peak in PAs is not consistent with NAA. The signal likely originates from an N-acetyl group of one or more other chemicals such as N-acetylated sugars. Magn Reson Med 78:452-456, 2017. © 2016 International Society for Magnetic Resonance in Medicine. © 2016 International Society for Magnetic Resonance in Medicine.

  17. Progress toward acetate supplementation therapy for Canavan disease: glyceryl triacetate administration increases acetate, but not N-acetylaspartate, levels in brain.

    PubMed

    Mathew, Raji; Arun, Peethambaran; Madhavarao, Chikkathur N; Moffett, John R; Namboodiri, M A Aryan

    2005-10-01

    Canavan disease (CD) is a fatal genetic neurodegenerative disorder caused by mutations in the gene for aspartoacylase, an enzyme that hydrolyzes N-acetylaspartate (NAA) into L-aspartate and acetate. Because aspartoacylase is localized in oligodendrocytes, and NAA-derived acetate is incorporated into myelin lipids, we hypothesize that an acetate deficiency in oligodendrocytes is responsible for the pathology in CD, and we propose acetate supplementation as a possible therapy. In our preclinical efforts toward this goal, we studied the effectiveness of orally administered glyceryl triacetate (GTA) and calcium acetate for increasing acetate levels in the murine brain. The concentrations of brain acetate and NAA were determined simultaneously after intragastric administration of GTA. We found that the acetate levels in brain were increased in a dose- and time-dependent manner, with a 17-fold increase observed at 1 to 2 h in 20- to 21-day-old mice at a dose of 5.8 g/kg GTA. NAA levels in the brain were not significantly increased under these conditions. Studies using mice at varying stages of development showed that the dose of GTA required to maintain similarly elevated acetate levels in the brain increased with age. Also, GTA was significantly more effective as an acetate source than calcium acetate. Chronic administration of GTA up to 25 days of age did not result in any overt pathology in the mice. Based on these results and the current Food and Drug Administration-approved use of GTA as a food additive, we propose that it is a potential candidate for use in acetate supplementation therapy for CD.

  18. Dynamic relationship between neurostimulation and N-acetylaspartate metabolism in the human visual cortex: evidence that NAA functions as a molecular water pump during visual stimulation.

    PubMed

    Baslow, Morris H; Hrabe, Jan; Guilfoyle, David N

    2007-01-01

    N-acetyl-l-aspartic acid (NAA), an amino acid synthesized and stored primarily in neurons in the brain, has been proposed to be a molecular water pump (MWP) whose function is to rapidly remove water from neurons against a water gradient. In this communication, we describe the results of a functional (1)H proton magnetic resonance spectroscopy (fMRS) study, and provide evidence that in the human visual cortex, over a 10-min period of visual stimulation, there are stimulation-induced graded changes in the NAA MRS signal from that of a preceding 10-min baseline period with a decline in the NAA signal of 13.1% by the end of the 10-min stimulation period. Upon cessation of visual stimulation, the NAA signal gradually increases during a 10-min recovery period and once again approaches the baseline level. Because the NAA MRS signal reflects the NAA concentration, these changes indicate rapid focal changes in its concentration, and transient changes in its intercompartmental metabolism. These include its rates of synthesis and efflux from neurons and its hydrolysis by oligodendrocytes. During stimulation, the apparent rate of NAA efflux and hydrolysis increased 14.2 times, from 0.55 to 7.8 micromol g(-1) h(-1). During recovery, the apparent rate of synthesis increased 13.3 times, from 0.55 to 7.3 micromol g(-1) h(-1). The decline in the NAA signal during stimulation suggests that a rapid increase in the rate of NAA-obligated water release to extracellular fluid (ECF) is the initial and seminal event in response to neurostimulation. It is concluded that the NAA metabolic cycle in the visual cortex is intimately linked to rates of neuronal signaling, and that the functional cycle of NAA is associated with its release to ECF, thus supporting the hypothesis that an important function of the NAA metabolic cycle is that of an efflux MWP.

  19. Transcriptional regulation of N-acetylaspartate metabolism in the 5xFAD model of Alzheimer's disease: evidence for neuron-glia communication during energetic crisis.

    PubMed

    Zaroff, Samantha; Leone, Paola; Markov, Vladimir; Francis, Jeremy S

    2015-03-01

    N-acetylaspartate (NAA) provides a non-invasive clinical index of neuronal metabolic integrity across the entire neurodegenerative spectrum. While NAA function is not comprehensively defined, reductions in the brain are associated with compromised mitochondrial metabolism and are tightly linked to ATP. We have undertaken an analysis of abnormalities in NAA during early stage pathology in the 5xFAD mouse model of familial Alzheimer's disease and show here that dysregulated expression of the gene encoding for the rate-limiting NAA synthetic enzyme (Nat8L) is associated with deficits in mitochondrial oxidative phosphorylation in this model system. Downreguation of Nat8L is particularly pronounced in the 5xFAD hippocampus, and is preceded by a significant upregulation of oligodendrocytic aspartoacylase (aspa), which encodes for the sole known NAA-catabolizing enzyme in the brain. Reductions in 5xFAD NAA and Nat8L cannot be accounted for by discrepancies in either neuron content or activity of the substrate-providing malate-aspartate shuttle, thereby implicating transcriptional regulation in a coordinated response to pathological energetic crisis. A central role for ASPA in this response is supported by a parallel developmental analysis showing highly significant increases in Nat8L expression in an ASPA-null mouse model during a period of early postnatal development normally punctuated by the transcriptional upregulation of aspa. These results provide preliminary evidence of a signaling mechanism in Alzheimer's disease that involves cross talk between neurons and oligodendrocytes, and suggest that ASPA acts to negatively regulate Nat8L expression. This mechanism is proposed to be a fundamental means by which the brain conserves available substrate during energy crises. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. Reduction of N-acetylaspartate in the medial prefrontal cortex correlated with symptom severity in obsessive-compulsive disorder: meta-analyses of 1H-MRS studies

    PubMed Central

    Aoki, Yuta; Aoki, Ai; Suwa, Hiroshi

    2012-01-01

    Structural and functional neuroimaging findings suggest that disturbance of the cortico–striato–thalamo–cortical (CSTC) circuits may underlie obsessive-compulsive disorder (OCD). However, some studies with 1H-magnetic resonance spectroscopy (1H-MRS) reported altered level of N-acetylaspartate (NAA), they yielded inconsistency in direction and location of abnormality within CSTC circuits. We conducted a comprehensive literature search and a meta-analysis of 1H-MRS studies in OCD. Seventeen met the inclusion criteria for a meta-analysis. Data were separated by frontal cortex region: medial prefrontal cortex (mPFC), dorsolateral prefrontal cortex, orbitofrontal cortex, basal ganglia and thalamus. The mean and s.d. of the NAA measure were calculated for each region. A random effects model integrating 16 separate datasets with 225 OCD patients and 233 healthy comparison subjects demonstrated that OCD patients exhibit decreased NAA levels in the frontal cortex (P=0.025), but no significant changes in the basal ganglia (P=0.770) or thalamus (P=0.466). Sensitivity analysis in an anatomically specified subgroup consisting of datasets examining the mPFC demonstrated marginally significant reduction of NAA (P=0.061). Meta-regression revealed that NAA reduction in the mPFC was positively correlated with symptom severity measured by Yale–Brown Obsessive Compulsive Scale (P=0.011). The specific reduction of NAA in the mPFC and significant relationship between neurochemical alteration in the mPFC and symptom severity indicate that the mPFC is one of the brain regions that directly related to abnormal behavior in the pathophysiology of OCD. The current meta-analysis indicates that cortices and sub-cortices contribute in different ways to the etiology of OCD. PMID:22892718

  1. 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.

  2. Oligodendrocytes Do Not Export NAA-Derived Aspartate In Vitro.

    PubMed

    I Amaral, Ana; Hadera, Mussie Ghezu; Kotter, Mark; Sonnewald, Ursula

    2017-03-01

    Oligodendroglial cells are known to de-acetylate the N-acetylaspartate (NAA) synthesized and released by neurons and use it for lipid synthesis. However, the role of NAA regarding their intermediary metabolism remains poorly understood. Two hypotheses were proposed regarding the fate of aspartate after being released by de-acetylation: (1) aspartate is metabolized in the mitochondria of oligodendrocyte lineage cells; (2) aspartate is released to the medium. We report here that aspartoacylase mRNA expression increases when primary rat oligodendrocyte progenitor cells (OPCs) differentiate into mature cells in culture. Moreover, characterising metabolic functions of acetyl coenzyme A and aspartate from NAA catabolism in mature oligodendrocyte cultures after 5 days using isotope-labelled glucose after 5-days of differentiation we found evidence of extensive NAA metabolism. Incubation with [1,6- 13 C]glucose followed by gas chromatography-mass spectrometry and high performance liquid chromatography analyses of cell extracts and media in the presence and absence of NAA established that the acetate moiety produced by hydrolysis of NAA does not enter mitochondrial metabolism in the form of acetyl coenzyme A. We also resolved the controversy concerning the possible release of aspartate to the medium: aspartate is not released to the medium by oligodendrocytes in amounts detectable by our methods. Therefore we propose that: aspartate released from NAA joins the cytosolic aspartate pool rapidly and takes part in the malate-aspartate shuttle, which transports reducing equivalents from glycolysis into the mitochondria for ATP production and enters the tricarboxylic acid cycle at a slow rate.

  3. Reproducibility over a 1-month period of 1H-MR spectroscopic imaging NAA/Cr ratios in clinically stable multiple sclerosis patients.

    PubMed

    Mostert, J P; Blaauw, Y; Koch, M W; Kuiper, A J; Hoogduin, J M; De Keyser, J

    2008-08-01

    N-acetylaspartate/creatine (NAA/Cr) ratios, assessed with proton magnetic resonance spectroscopy, are increasingly used as a surrogate marker for axonal dysfunction and degeneration in multiple sclerosis (MS). The purpose of this study was to test short-time reproducibility of NAA/Cr ratios in patients with clinically stable MS. In 35 MS patients we analysed NAA/Cr ratios obtained with (1)H-MR spectroscopic imaging at the centrum semiovale either with lateral ventricles partially included (group 1; n=15) or more cranially with no ventricles included (group 2; n=20). To test short-term reproducibility of the NAA/Cr measurements, patients were scanned twice 4 weeks apart. We determined mean NAA/Cr and Cho/Cr ratios of 12 grey matter and 24 white matter voxels. Mean NAA/Cr ratios of both the white and grey matter did not change after 4 weeks. Overall 4-week reproducibility of the NAA/Cr ratio, expressed as coefficient of variation, was 4.8% for grey matter and 3.5% for white matter. Reproducibility of cranial scanning of the ventricles was slightly better than with cerebrospinal fluid included. Our study shows good short-term reproducibility of NAA/Cr ratio measurements in the centrum semiovale, which supports the reliability of this technique for longitudinal studies.

  4. White matter NAA/Cho and Cho/Cr ratios at MR spectroscopy are predictive of motor outcome in preterm infants.

    PubMed

    Kendall, Giles S; Melbourne, Andrew; Johnson, Samantha; Price, David; Bainbridge, Alan; Gunny, Roxanna; Huertas-Ceballos, Angela; Cady, Ernest B; Ourselin, Sebastian; Marlow, Neil; Robertson, Nicola J

    2014-04-01

    To determine (a) whether diffuse white matter injury of prematurity is associated with an increased choline (Cho)-to-creatine (Cr) ratio and a reduced N-acetylaspartate (NAA)-to-Cho ratio and whether these measures can be used as biomarkers of outcome and (b) if changes in peak area metabolite ratios at magnetic resonance (MR) spectroscopy are associated with changes in T2 and fractional anisotropy (FA) at MR imaging. The local ethics committee approved this study, and informed parental consent was obtained for each infant. At term-equivalent age, 43 infants born at less than 32 weeks gestation underwent conventional and quantitative diffusion-tensor and T2-weighted MR imaging. Single-voxel point-resolved proton (hydrogen 1) MR spectroscopy was performed from a 2-cm(3) voxel centered in the posterior periventricular white matter. Outcome was evaluated by using Bayley scales at a corrected age of 1 year. Associations were investigated with Pearson product moment or Spearman rank order correlation. Differences in ratios in infants with and infants without impairment were tested by using t tests. NAA/Cho and Cho/Cr ratios correlated with the scaled gross motor score and the composite motor score, independent of gestational age (P < .05). FA at diffusion-tensor MR imaging and T2 at MR imaging correlated with the NAA/Cho ratio (P < .05 for both) but not with the Cho/Cr ratio. Infants with motor scores of less than 85 (impaired) had an increased Cho/Cr ratio (P < .03) and a reduced NAA/Cho ratio (P < .01) compared to those without impairment. A combination of increased Cho/Cr ratio and decreased NAA/Cho ratio predicted impaired motor outcome at a corrected age of 1 year with a sensitivity of 0.80 (95% confidence interval [CI]: 0.57, 0.94) and a specificity of 0.80 (95% CI: 0.66, 0.88). The combination of Cho/Cr and NAA/Cho ratios measured in the posterior periventricular white matter at term-equivalent age is predictive of motor outcome at 1 year in infants born at less

  5. The neuronal metabolite NAA regulates histone H3 methylation in oligodendrocytes and myelin lipid composition

    PubMed Central

    Singhal, N. K.; Huang, H.; Li, S.; Clements, R.; Gadd, J.; Daniels, A.; Kooijman, E. E.; Bannerman, P.; Burns, T.; Guo, F.; Pleasure, D.; Freeman, E.; Shriver, L.

    2017-01-01

    The neuronal mitochondrial metabolite N-acetylaspartate (NAA) is decreased in the multiple sclerosis (MS) brain. NAA is synthesized in neurons by the enzyme N-acetyltransferase-8-like (NAT8L) and broken down in oligodendrocytes by aspartoacylase (ASPA) into acetate and aspartate. We have hypothesized that NAA links the metabolism of axons with oligodendrocytes to support myelination. To test this hypothesis, we performed lipidomic analyses using liquid chromatography–tandem mass spectrometry (LC–MS/MS) and high-performance thin-layer chromatography (HPTLC) to identify changes in myelin lipid composition in postmortem MS brains and in NAT8L knockout (NAT8L−/−) mice which do not synthesize NAA. We found reduced levels of sphingomyelin in MS normal appearing white matter that mirrored decreased levels of NAA. We also discovered decreases in the amounts of sphingomyelin and sulfatide lipids in the brains of NAT8L−/− mice compared to controls. Metabolomic analysis of primary cultures of oligodendrocytes treated with NAA revealed increased levels of α-ketoglutarate, which has been reported to regulate histone demethylase activity. Consistent with this, NAA treatment resulted in alterations in the levels of histone H3 methylation, including H3K4me3, H3K9me2, and H3K9me3. The H3K4me3 histone mark regulates cellular energetics, metabolism, and growth, while H3K9me3 has been linked to alterations in transcriptional repression in developing oligodendrocytes. We also noted the NAA treatment was associated with increases in the expression of genes involved in sulfatide and sphingomyelin synthesis in cultured oligodendrocytes. This is the first report demonstrating that neuronal-derived NAA can signal to the oligodendrocyte nucleus. These data suggest that neuronal-derived NAA signals through epigenetic mechanisms in oligodendrocytes to support or maintain myelination. PMID:27709268

  6. The neuronal metabolite NAA regulates histone H3 methylation in oligodendrocytes and myelin lipid composition.

    PubMed

    Singhal, N K; Huang, H; Li, S; Clements, R; Gadd, J; Daniels, A; Kooijman, E E; Bannerman, P; Burns, T; Guo, F; Pleasure, D; Freeman, E; Shriver, L; McDonough, J

    2017-01-01

    The neuronal mitochondrial metabolite N-acetylaspartate (NAA) is decreased in the multiple sclerosis (MS) brain. NAA is synthesized in neurons by the enzyme N-acetyltransferase-8-like (NAT8L) and broken down in oligodendrocytes by aspartoacylase (ASPA) into acetate and aspartate. We have hypothesized that NAA links the metabolism of axons with oligodendrocytes to support myelination. To test this hypothesis, we performed lipidomic analyses using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and high-performance thin-layer chromatography (HPTLC) to identify changes in myelin lipid composition in postmortem MS brains and in NAT8L knockout (NAT8L -/- ) mice which do not synthesize NAA. We found reduced levels of sphingomyelin in MS normal appearing white matter that mirrored decreased levels of NAA. We also discovered decreases in the amounts of sphingomyelin and sulfatide lipids in the brains of NAT8L -/- mice compared to controls. Metabolomic analysis of primary cultures of oligodendrocytes treated with NAA revealed increased levels of α-ketoglutarate, which has been reported to regulate histone demethylase activity. Consistent with this, NAA treatment resulted in alterations in the levels of histone H3 methylation, including H3K4me3, H3K9me2, and H3K9me3. The H3K4me3 histone mark regulates cellular energetics, metabolism, and growth, while H3K9me3 has been linked to alterations in transcriptional repression in developing oligodendrocytes. We also noted the NAA treatment was associated with increases in the expression of genes involved in sulfatide and sphingomyelin synthesis in cultured oligodendrocytes. This is the first report demonstrating that neuronal-derived NAA can signal to the oligodendrocyte nucleus. These data suggest that neuronal-derived NAA signals through epigenetic mechanisms in oligodendrocytes to support or maintain myelination.

  7. Is NAA reduction in normal contralateral cerebral tissue in stroke patients dependent on underlying risk factors?

    PubMed

    Walker, P M; Ben Salem, D; Giroud, M; Brunotte, F

    2006-05-01

    This retrospective study investigated the dependence of N-acetyl aspartate (NAA) ratios on risk factors for cerebral vasculopathy such as sex, age, hypertension, diabetes mellitus, carotid stenosis, and dyslipidaemia, which may have affected brain vessels and induced metabolic brain abnormalities prior to stroke. We hypothesise that in stroke patients metabolic alterations in the apparently normal contralateral brain are dependent on the presence or not of such risk factors. Fifty nine patients (31 male, 28 female: 58.8+/-16.1 years old) with cortical middle cerebral artery (MCA) territory infarction were included. Long echo time chemical shift imaging spectroscopy was carried out on a Siemens 1.5 T Magnetom Vision scanner using a multi-voxel PRESS technique. Metabolite ratios (NAA/choline, NAA/creatine, lactate/choline, etc) were studied using uni- and multivariate analyses with respect to common risk factors. The influence of age, stroke lesion size, and time since stroke was studied using a linear regression approach. Age, sex, and hypertension all appeared to individually influence metabolite ratios, although only hypertension was significant after multivariate analysis. In both basal ganglia and periventricular white matter regions in apparently normal contralateral brain, the NAA/choline ratio was significantly lower in hypertensive (1.37+/-0.16 and 1.50+/-0.19, respectively) than in normotensive patients (1.72+/-0.19 and 1.85+/-0.15, respectively). Regarding MCA infarction, contralateral tissue remote from the lesion behaves abnormally in the presence of hypertension, the NAA ratios in hypertensive patients being significantly lower. These data suggest that hypertension may compromise the use of contralateral tissue data as a reference for comparison with ischaemic tissue.

  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. 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.

  10. 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

  11. Methamphetamine-induced neuronal protein NAT8L is the NAA biosynthetic enzyme: implications for specialized acetyl coenzyme A metabolism in the CNS.

    PubMed

    Ariyannur, Prasanth S; Moffett, John R; Manickam, Pachiappan; Pattabiraman, Nagarajan; Arun, Peethambaran; Nitta, Atsumi; Nabeshima, Toshitaka; Madhavarao, Chikkathur N; Namboodiri, Aryan M A

    2010-06-04

    N-acetylaspartate (NAA) is a concentrated, neuron-specific brain metabolite routinely used as a magnetic resonance spectroscopy marker for brain injury and disease. Despite decades of research, the functional roles of NAA remain unclear. Biochemical investigations over several decades have associated NAA with myelin lipid synthesis and energy metabolism. However, studies have been hampered by an inability to identify the gene for the NAA biosynthetic enzyme aspartate N-acetyltransferase (Asp-NAT). A very recent report has identified Nat8l as the gene encoding Asp-NAT and confirmed that the only child diagnosed with a lack of NAA on brain magnetic resonance spectrograms has a 19-bp deletion in this gene. Based on in vitro Nat8l expression studies the researchers concluded that many previous biochemical investigations have been technically flawed and that NAA may not be associated with brain energy or lipid metabolism. In studies done concurrently in our laboratory we have demonstrated via cloning, expression, specificity for acetylation of aspartate, responsiveness to methamphetamine treatment, molecular modeling and comparative immunolocalization that NAT8L is the NAA biosynthetic enzyme Asp-NAT. We conclude that NAA is a major storage and transport form of acetyl coenzyme A specific to the nervous system, thus linking it to both lipid synthesis and energy metabolism. Published by Elsevier B.V.

  12. Posterior Insular Molecular Changes in Myofascial Pain

    PubMed Central

    Gerstner, G.E.; Gracely, R.H.; Deebajah, A.; Ichesco, E.; Quintero, A.; Clauw, D.J.; Sundgren, P.C.

    2012-01-01

    Temporomandibular disorders (TMD) include craniocervical pain conditions with unclear etiologies. Central changes are suspected; however, few neuroimaging studies of TMD exist. Single-voxel proton magnetic resonance spectroscopy (1H-MRS) was used before and after pressure-pain testing to assess glutamate (Glu), glutamine (Gln), N-acetylaspartate (NAA), and choline (Cho) levels in the right and left posterior insulae of 11 individuals with myofascial TMD and 11 matched control individuals. Glu levels were significantly lower in all individuals after pain testing. Among those with TMD, left-insular Gln levels were related to reported pain, left posterior insular NAA and Cho levels were significantly higher at baseline than in control individuals, and NAA levels were significantly correlated with pain-symptom duration, suggesting adaptive changes. The results suggest that significant central cellular and molecular changes can occur in individuals with TMD. PMID:22451533

  13. Role of Increased n-acetylaspartate Levels in Cancer

    PubMed Central

    Zand, Behrouz; Previs, Rebecca A.; Zacharias, Niki M.; Rupaimoole, Rajesha; Mitamura, Takashi; Nagaraja, Archana Sidalaghatta; Guindani, Michele; Dalton, Heather J.; Yang, Lifeng; Baddour, Joelle; Achreja, Abhinav; Hu, Wei; Pecot, Chad V.; Ivan, Cristina; Wu, Sherry Y.; McCullough, Christopher R.; Gharpure, Kshipra M.; Shoshan, Einav; Pradeep, Sunila; Mangala, Lingegowda S.; Rodriguez-Aguayo, Cristian; Wang, Ying; Nick, Alpa M.; Davies, Michael A.; Armaiz-Pena, Guillermo; Liu, Jinsong; Lutgendorf, Susan K.; Baggerly, Keith A.; Eli, Menashe Bar; Lopez-Berestein, Gabriel; Nagrath, Deepak; Bhattacharya, Pratip K.

    2016-01-01

    Background: The clinical and biological effects of metabolic alterations in cancer are not fully understood. Methods: In high-grade serous ovarian cancer (HGSOC) samples (n = 101), over 170 metabolites were profiled and compared with normal ovarian tissues (n = 15). To determine NAT8L gene expression across different cancer types, we analyzed the RNA expression of cancer types using RNASeqV2 data available from the open access The Cancer Genome Atlas (TCGA) website (http://www.cbioportal.org/public-portal/). Using NAT8L siRNA, molecular techniques and histological analysis, we determined cancer cell viability, proliferation, apoptosis, and tumor growth in in vitro and in vivo (n = 6–10 mice/group) settings. Data were analyzed with the Student’s t test and Kaplan-Meier analysis. Statistical tests were two-sided. Results: Patients with high levels of tumoral NAA and its biosynthetic enzyme, aspartate N-acetyltransferase (NAT8L), had worse overall survival than patients with low levels of NAA and NAT8L. The overall survival duration of patients with higher-than-median NAA levels (3.6 years) was lower than that of patients with lower-than-median NAA levels (5.1 years, P = .03). High NAT8L gene expression in other cancers (melanoma, renal cell, breast, colon, and uterine cancers) was associated with worse overall survival. NAT8L silencing reduced cancer cell viability (HEYA8: control siRNA 90.61%±2.53, NAT8L siRNA 39.43%±3.00, P < .001; A2780: control siRNA 90.59%±2.53, NAT8L siRNA 7.44%±1.71, P < .001) and proliferation (HEYA8: control siRNA 74.83%±0.92, NAT8L siRNA 55.70%±1.54, P < .001; A2780: control siRNA 50.17%±4.13, NAT8L siRNA 26.52%±3.70, P < .001), which was rescued by addition of NAA. In orthotopic mouse models (ovarian cancer and melanoma), NAT8L silencing reduced tumor growth statistically significantly (A2780: control siRNA 0.52 g±0.15, NAT8L siRNA 0.08 g±0.17, P < .001; HEYA8: control siRNA 0.79 g±0.42, NAT8L siRNA 0.24 g±0.18, P = .008, A

  14. Effects of electromagnetic radiation produced by 3G mobile phones on rat brains: magnetic resonance spectroscopy, biochemical, and histopathological evaluation.

    PubMed

    Dogan, M; Turtay, M G; Oguzturk, H; Samdanci, E; Turkoz, Y; Tasdemir, S; Alkan, A; Bakir, S

    2012-06-01

    The effects of electromagnetic radiation (EMR) produced by a third-generation (3G) mobile phone (MP) on rat brain tissues were investigated in terms of magnetic resonance spectroscopy (MRS), biochemistry, and histopathological evaluations. The rats were randomly assigned to two groups: Group 1 is composed of 3G-EMR-exposed rats (n = 9) and Group 2 is the control group (n = 9). The first group was subjected to EMR for 20 days. The control group was not exposed to EMR. Choline (Cho), creatinin (Cr), and N-acetylaspartate (NAA) levels were evaluated by MRS. Catalase (CAT) and glutathione peroxidase (GSH-Px) enzyme activities were measured by spectrophotometric method. Histopathological analyses were carried out to evaluate apoptosis in the brain tissues of both groups. In MRS, NAA/Cr, Cho/Cr, and NAA/Cho ratios were not significantly different between Groups 1 and 2. Neither the oxidative stress parameters, CAT and GSH-Px, nor the number of apoptotic cells were significantly different between Groups 1 and 2. Usage of short-term 3G MP does not seem to have a harmful effect on rat brain tissue.

  15. 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.

  16. 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).

  17. 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

  18. 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.

  19. 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

  20. 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.

  1. 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

  2. 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.

  3. Neurochemistry in shiverer mouse depicted on MR spectroscopy.

    PubMed

    Takanashi, Jun-ichi; Nitta, Nobuhiro; Iwasaki, Nobuaki; Saito, Shigeyoshi; Tanaka, Ryuta; Barkovich, A James; Aoki, Ichio

    2014-06-01

    To evaluate the neurochemical changes associated with hypomyelination, especially to clarify whether increased total N-acetylaspartate (tNAA) with decreased choline (Cho) observed in the thalamus of msd mice with the plp1 mutation is a common finding for hypomyelinating disorders. We performed magnetic resonance imaging (MRI) and proton MR spectroscopy ((1) H-MRS) of the thalamus and cortex of postnatal 12-week shiverer mice devoid of myelin basic protein (mbp), heterozygous and wild-type mice with a 7.0T magnet. Luxol Fast Blue staining and immunohistochemical analysis with anti-Mbp, Gfap, Olig2, and NeuN antibodies were also performed. In the thalamus, decreased Cho and normal tNAA were observed in shiverer mice. In the cortex, tNAA, Cho, and glutamate were decreased in shiverer mice. Histological and immunohistochemical analysis of shiverer mice brains revealed hypomyelination in the thalamus, white matter, and cortex; astrogliosis and an increased number of total oligodendrocytes in the white matter; and a decreased number of neurons in the cortex. The reduction of Cho on (1) H-MRS might be a common marker for hypomyelinating disorders. A normal tNAA level in the thalamus of shiverer mice might be explained by the presence of mature oligodendrocytes, which enable neuron-to-oligodendrocyte NAA transport or NAA catabolism. Copyright © 2013 Wiley Periodicals, Inc.

  4. 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.

  5. 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.

  6. The Molecular Basis of Canavan Disease: Aspartoacylase Enzyme Characteristics

    DTIC Science & Technology

    2006-01-01

    this conclusion by observing that children with certain neurodegenerative conditions also had N-acetylaspartic aciduria , abnormally high levels of NAA...in the urine. In the late 1980’s, N-acetylaspartic aciduria and deficient ASPA activity in cultured fibroblasts were linked to cases of cerebral...symptoms of CD are found in other leukodystrophies and neurodegenerative disorders, N-acetylaspartic aciduria is exclusive to CD. Slightly elevated

  7. Elevated Myo-Inositol, Choline, and Glutamate Levels in the Associative Striatum of Antipsychotic-Naive Patients With First-Episode Psychosis: A Proton Magnetic Resonance Spectroscopy Study With Implications for Glial Dysfunction

    PubMed Central

    Plitman, Eric; de la Fuente-Sandoval, Camilo; Reyes-Madrigal, Francisco; Chavez, Sofia; Gómez-Cruz, Gladys; León-Ortiz, Pablo; Graff-Guerrero, Ariel

    2016-01-01

    Glial disturbances are highly implicated in the pathophysiology of schizophrenia and may be linked with glutamatergic dysregulation. Myo-inositol (mI), a putative marker of glial cells, and choline (Cho), representative of membrane turnover, are both present in larger concentrations within glial cells than in neurons, and their elevation is often interpreted to reflect glial activation. Proton magnetic resonance spectroscopy (1H-MRS) allows for the evaluation of mI, Cho, glutamate, glutamate + glutamine (Glx), and N-acetylaspartate (NAA). A collective investigation of these measures in antipsychotic-naive patients experiencing their first nonaffective episode of psychosis (FEP) can improve the understanding of glial dysfunction and its implications in the early stages of schizophrenia. 3-Tesla 1H-MRS (echo time = 35ms) was performed in 60 antipsychotic-naive patients with FEP and 60 age- and sex-matched healthy controls. mI, Cho, glutamate, Glx, and NAA were estimated using LCModel and corrected for cerebrospinal fluid composition within the voxel. mI, Cho, and glutamate were elevated in the FEP group. After correction for multiple comparisons, mI positively correlated with grandiosity. The relationships between mI and glutamate, and Cho and glutamate, were more positive in the FEP group. These findings are suggestive of glial activation in the absence of neuronal loss and may thereby provide support for the presence of a neuroinflammatory process within the early stages of schizophrenia. Dysregulation of glial function might result in the disruption of glutamatergic neurotransmission, which may influence positive symptomatology in patients with FEP. PMID:26320195

  8. 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.

  9. 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).

  10. Single voxel magnetic resonance spectroscopy at 3 Tesla in a memory disorders clinic: early right hippocampal NAA/Cr loss in mildly impaired subjects.

    PubMed

    Caserta, Maria T; Ragin, Ann; Hermida, Adriana P; Ahrens, R John; Wise, Leon

    2008-11-30

    In this study, we use magnetic resonance spectroscopy (MRS) at 3 Tesla to measure N-acetyl aspartate (NAA), myo-inositol (mI) and choline (Cho) to creatine (Cr) ratios in R (right) and L (left) hippocampi (H) in 8 mildly memory impaired (MMI), 6 probable Alzheimer's Disease (PRAD), and 17 control subjects. NAA/Cr was significantly reduced in the RH in the MMI group and bilaterally in the PRAD group vs. controls. No other metabolite differences were noted between the three groups. Five MMI subjects have converted to PRAD in follow-up. These findings suggest that RH NAA/Cr ratios measured at 3 Tesla may be a sensitive marker of future progression to dementia in a clinically defined population with isolated memory complaints.

  11. An Open-Label Exploratory Study with Memantine: Correlation between Proton Magnetic Resonance Spectroscopy and Cognition in Patients with Mild to Moderate Alzheimer's Disease

    PubMed Central

    Gordon, Marc L.; Kingsley, Peter B.; Goldberg, Terry E.; Koppel, Jeremy; Christen, Erica; Keehlisen, Lynda; Kohn, Nina; Davies, Peter

    2012-01-01

    Aim To characterize progression of Alzheimer's disease (AD) using proton magnetic resonance spectroscopy (1H MRS). Methods Eleven subjects with mild to moderate AD underwent neurocognitive testing and single-voxel 1H MRS from the precuneus and posterior cingulate region at baseline, after 24 weeks of monotherapy with a cholinesterase inhibitor, and after another 24 weeks of combination therapy with open-label memantine and a cholinesterase inhibitor. Baseline metabolites [N-acetylaspartate (NAA), myo-inositol (mI), choline (Cho), and creatine (Cr)] and their ratios in AD subjects were compared with those of an age-matched control group of 28 cognitively normal subjects. Results AD subjects had significantly higher mI/Cr and lower NAA, NAA/Cr, NAA/Cho, and NAA/mI. Baseline Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) scores significantly correlated with NAA/Cr, mI/Cr, and NAA/mI. There was an increase in mI and a decrease in NAA/mI, but no significant change in other metabolites or ratios, or neurocognitive measures, when memantine was added to a cholinesterase inhibitor. Conclusion Metabolite ratios significantly differed between AD and control subjects. Baseline metabolite ratios correlated with function (ADCS-ADL). There was an increase in mI and a decrease in NAA/mI, but no changes in other metabolites, ratios, or cognitive measures, when memantine was added to a cholinesterase inhibitor. PMID:22962555

  12. 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.

  13. Role of diffusion tensor imaging or magnetic resonance spectroscopy in the diagnosis and disability assessment of amyotrophic lateral sclerosis.

    PubMed

    Liu, Chanchan; Jiang, Rifeng; Yi, Xiyan; Zhu, Wenzhen; Bu, Bitao

    2015-01-15

    To compare the results of magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI) in amyotrophic lateral sclerosis (ALS) patients. Nineteen ALS patients and thirteen age-matched healthy controls underwent MRS and DTI between October 2013 and July 2014. Fractional anisotropy (FA), apparent diffusion coefficient (ADC), N-acetylaspartate (NAA), choline (Cho), and creatine (Cr) were collected as the quantitative results of the imaging study. The ALS functional rating scale-revised (ALSFRS-R) and disease progression rate were evaluated to assess patients' disability. The imaging study results were compared between ALS patients and healthy controls. The relationship between disability assessment and imaging study results was analyzed. NAA/Cr in the motor cortex and FA in the corticospinal tract (CST) of both sides were significantly lower in patients than controls. There was no significant difference between the two groups in Cho/Cr, tract length, tract volume, ADC or NAA. No relationship was found between ALSFRS-R and FA (r=0.243, p=0.316) in the right CST; NAA (r=0.095, p=0.699) or NAA/Cr (r=0.172, p=0.481) in the left motor cortex; or NAA (r=0.320, p=0.182) or NAA/Cr (r=0.193, p=0.492) in the right motor cortex. There was no relationship between the disease progression rate and FA, NAA, or NAA/Cr on either side. NAA/Cr and FA can help diagnose ALS. Regional brain NAA/Cr and FA values could not assess the ALSFRS-R or disease progression rate. Copyright © 2014 Elsevier B.V. All rights reserved.

  14. N-acetylaspartate (NAA) levels in selected areas of the brain in patients with chronic schizophrenia treated with typical and atypical neuroleptics: a proton magnetic resonance spectroscopy (1H MRS) study.

    PubMed

    Szulc, Agata; Galińska, Beata; Tarasów, Eugeniusz; Kubas, Bozena; Dzienis, Wojciech; Konarzewska, Beata; Poplawska, Regina; Tomczak, Anna A; Czernikiewicz, Andrzej; Walecki, Jerzy

    2007-05-01

    NAA, marker of neurons integrity and viability, is one of the most important brain metabolites visible in 1H MRS. In most studies of schizophrenia, the decrease of NAA level was observed in the temporal, frontal lobes and in the thalamus. This finding was observed more often among chronic patients, what suggests the influence of disease duration or the effect of neuroleptic treatment. The aim of the present study was the comparison of NAA levels in brain of schizophrenic patients taking typical and atypical neuroleptics. We analyzed the NAA levels in selected brain areas in 58 schizophrenic patients and 21 healthy controls. 10 patients were treated with typical neuroleptics, 10 patients with clozapine, 17 received olanzapine and 21 - risperidone. 1H MRS was performed on a 1,5 MR scanner with PRESS sequence. Voxels of 2x2x2 cm were localized in the left frontal, left temporal lobe and left thalamus. There were no differences in NAA levels between patients on typical and atypical medications analyzed together and separately (olanzapine, clozapine and risperidone groups). We also did not find any differences between patients taking selected atypical neuroleptics and controls. The NAA level in the thalamus in the group of patients receiving typical antipsychotics was the lowest among all groups and differed significantly from healthy controls. The results of our study suggest that atypical neuroleptics may have favorable effect on NAA concentration in brain of schizophrenic patients. Decrease in NAA level in patients taking typical medication may be caused by the progression of the disease or by the direct action of these drugs.

  15. 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.

  16. 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

  17. Regional metabolic changes in the hippocampus and posterior cingulate area detected with 3-Tesla magnetic resonance spectroscopy in patients with mild cognitive impairment and Alzheimer disease.

    PubMed

    Wang, Zhiqun; Zhao, Cheng; Yu, Lei; Zhou, Weidong; Li, Kuncheng

    2009-04-01

    Magnetic resonance spectroscopy (MRS) plays an important role in early diagnosis of Alzheimer disease (AD). There are many reports on MRS studies among individuals with AD and mild cognitive impairment (MCI). However, very few studies have compared spectroscopic data of different limbic regions among AD and MCI subjects. To compare metabolite changes of different regions in the brain of AD and MCI patients by using 3.0 T short-echo-time MRS. Metabolite ratios in the hippocampus and posterior cingulate area were compared in a group of patients with AD (n=16), MCI (n=16), and normal subjects as a control group (n=16). Clinical neuropsychological tests were measured in all subjects. In the hippocampus, there were significant differences in N-acetylaspartate (NAA)/creatine (Cr), myo-inositol (mI)/Cr, and mI/NAA ratios among the three groups. However, there were no significant differences in choline (Cho)/Cr ratio among the three groups. In the posterior cingulate area, there were no significant differences in the NAA/Cr, Cho/Cr, and mI/Cr ratios among the three groups. However, there were significant differences in mI/NAA ratio between patients with AD and the control group, and between the AD and MCI groups. In addition, there was significant correlation between mI/NAA ratio and Mini Mental Status Exam (MMSE) score in subjects with AD and MCI. The study reveals that the elevation of mI/NAA ratio in the hippocampus is more significant than that in the posterior cingulate area, which corresponds to the pathologic procession of AD. The ratios of mI/NAA in the hippocampus and in the posterior cingulate area together provide valuable discrimination among the three groups (AD, MCI, and controls). There is a significant correlation between mI/NAA ratio and cognitive decline.

  18. [Magnetic resonance spectroscopy of metabolic changes in mice brain after 2-deoxy-D-glucose injection].

    PubMed

    Moshkin, M P; Akulov, A E; Petrovskiĭ, D V; Saĭk, O V; Petrovskiĭ, E D; Savelov, A A; Koptug, I V

    2012-10-01

    In vivo proton magnetic resonance spectroscopy (1H MRS) of ICR male mice was used to study the brain (hippocampus) metabolic response to the acute deficiency of the available energy or to the pro-inflammatory stimulus. Inhibition of glycolysis by means of an intraperitoneal injection with 2-deoxy-D-glucose (2DG) reduced the levels of gamma-aminobutiric acid (GABA), N-acetylaspartate (NAA) and choline compounds, and at the same time increased the levels of glutamate and glutamine. An opposite effect was found after injection with bacterial lipopolysaccharide (LPS)--a very common pro-inflammatory inducer. An increase in the amounts of GABA, NAA and choline compounds in the brain occurred three hours after the injection of LPS. Different metabolic responses to the energy deficiency and the pro-inflammatory stimuli can explain the contradictory results of the brain MRS studies under neurodegenerative pathology, which is accompanied by both mitochondrial dysfunction and inflammation. Prevalence of the excitatory metabolites such as glutamate and glutamine in 2DG treated mice is in good agreement with excitation observed during temporary reduction of the available energy under acute hypoxia or starvation. In turn, LPS, as an inducer of the sickness behavior, shifts brain metabolic pattern to prevalence of the inhibitory neurotransmitter GABA.

  19. Evaluation of disease progression in INCL by MR spectroscopy.

    PubMed

    Baker, Eva H; Levin, Sondra W; Zhang, Zhongjian; Mukherjee, Anil B

    2015-08-01

    Infantile neuronal ceroid lipofuscinosis (INCL) is a devastating neurodegenerative storage disease caused by palmitoyl-protein thioesterase-1 deficiency, which impairs degradation of palmitoylated proteins (constituents of ceroid) by lysosomal hydrolases. Consequent lysosomal ceroid accumulation leads to neuronal injury. As part of a pilot study to evaluate treatment benefits of cysteamine bitartrate and N-acetylcysteine, we quantitatively measured brain metabolite levels using magnetic resonance spectroscopy (MRS). A subset of two patients from a larger treatment and follow-up study underwent serial quantitative single-voxel MRS examinations of five anatomical sites. Three echo times were acquired in order to estimate metabolite T2. Measured metabolite levels included correction for partial volume of cerebrospinal fluid. Comparison of INCL patients was made to a reference group composed of asymptomatic and minimally symptomatic Niemann-Pick disease type C patients. In INCL patients, N-acetylaspartate (NAA) was abnormally low at all locations upon initial measurement, and further declined throughout the follow-up period. In the cerebrum (affected early in the disease course), choline and myo-inositol were initially elevated and fell during the follow-up period, whereas in the cerebellum and brainstem (affected later), choline and myo-inositol were initially normal and rose subsequently. Choline and myo-inositol levels in our patients are consistent with patterns of neuroinflammation observed in two INCL mouse models. Low, persistently declining NAA was expected based on the progressive, irreversible nature of the disease. Progression of metabolite levels in INCL has not been previously quantified; therefore the results of this study serve as a reference for quantitative evaluation of future therapeutic interventions.

  20. 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.

  1. Elevated Myo-Inositol, Choline, and Glutamate Levels in the Associative Striatum of Antipsychotic-Naive Patients With First-Episode Psychosis: A Proton Magnetic Resonance Spectroscopy Study With Implications for Glial Dysfunction.

    PubMed

    Plitman, Eric; de la Fuente-Sandoval, Camilo; Reyes-Madrigal, Francisco; Chavez, Sofia; Gómez-Cruz, Gladys; León-Ortiz, Pablo; Graff-Guerrero, Ariel

    2016-03-01

    Glial disturbances are highly implicated in the pathophysiology of schizophrenia and may be linked with glutamatergic dysregulation. Myo-inositol (mI), a putative marker of glial cells, and choline (Cho), representative of membrane turnover, are both present in larger concentrations within glial cells than in neurons, and their elevation is often interpreted to reflect glial activation. Proton magnetic resonance spectroscopy ((1)H-MRS) allows for the evaluation of mI, Cho, glutamate, glutamate + glutamine (Glx), and N-acetylaspartate (NAA). A collective investigation of these measures in antipsychotic-naive patients experiencing their first nonaffective episode of psychosis (FEP) can improve the understanding of glial dysfunction and its implications in the early stages of schizophrenia. 3-Tesla (1)H-MRS (echo time = 35 ms) was performed in 60 antipsychotic-naive patients with FEP and 60 age- and sex-matched healthy controls. mI, Cho, glutamate, Glx, and NAA were estimated using LCModel and corrected for cerebrospinal fluid composition within the voxel. mI, Cho, and glutamate were elevated in the FEP group. After correction for multiple comparisons, mI positively correlated with grandiosity. The relationships between mI and glutamate, and Cho and glutamate, were more positive in the FEP group. These findings are suggestive of glial activation in the absence of neuronal loss and may thereby provide support for the presence of a neuroinflammatory process within the early stages of schizophrenia. Dysregulation of glial function might result in the disruption of glutamatergic neurotransmission, which may influence positive symptomatology in patients with FEP. © The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  2. Purification and characterization of aspartate N-acetyltransferase: A critical enzyme in brain metabolism.

    PubMed

    Wang, Qinzhe; Zhao, Mojun; Parungao, Gwenn G; Viola, Ronald E

    2016-03-01

    Canavan disease (CD) is a neurological disorder caused by an interruption in the metabolism of N-acetylaspartate (NAA). Numerous mutations have been found in the enzyme that hydrolyzes NAA, and the catalytic activity of aspartoacylase is significantly impaired in CD patients. Recent studies have also supported an important role in CD for the enzyme that catalyzes the synthesis of NAA in the brain. However, previous attempts to study this enzyme had not succeeded in obtaining a soluble, stable and active form of this membrane-associated protein. We have now utilized fusion constructs with solubilizing protein partners to obtain an active and soluble form of aspartate N-acetyltransferase. Characterization of the properties of this enzyme has set the stage for the development of selective inhibitors that can lower the elevated levels of NAA that are observed in CD patients and potentially serve as a new treatment therapy. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. Absence of age-related prefrontal NAA change in adults with autism spectrum disorders.

    PubMed

    Aoki, Y; Abe, O; Yahata, N; Kuwabara, H; Natsubori, T; Iwashiro, N; Takano, Y; Inoue, H; Kawakubo, Y; Gonoi, W; Sasaki, H; Murakami, M; Katsura, M; Nippashi, Y; Takao, H; Kunimatsu, A; Matsuzaki, H; Tsuchiya, K J; Kato, N; Kasai, K; Yamasue, H

    2012-10-23

    Atypical trajectory of brain growth in autism spectrum disorders (ASDs) has been recognized as a potential etiology of an atypical course of behavioral development. Numerous neuroimaging studies have focused on childhood to investigate atypical age-related change of brain structure and function, because it is a period of neuron and synapse maturation. Recent studies, however, have shown that the atypical age-related structural change of autistic brain expands beyond childhood and constitutes neural underpinnings for lifelong difficulty to behavioral adaptation. Thus, we examined effects of aging on neurochemical aspects of brain maturation using 3-T proton magnetic resonance spectroscopy ((1)H-MRS) with single voxel in the medial prefrontal cortex (PFC) in 24 adult men with non-medicated high-functioning ASDs and 25 age-, IQ- and parental-socioeconomic-background-matched men with typical development (TD). Multivariate analyses of covariance demonstrated significantly high N-acetylaspartate (NAA) level in the ASD subjects compared with the TD subjects (F=4.83, P=0.033). The low NAA level showed a significant positive correlation with advanced age in the TD group (r=-0.618, P=0.001), but was not evident among the ASD individuals (r=0.258, P=0.223). Fisher's r-to-z transformation showed a significant difference in the correlations between the ASD and TD groups (Z=-3.23, P=0.001), which indicated that the age-NAA relationship was significantly specific to people with TD. The current (1)H-MRS study provided new evidence that atypical age-related change of neurochemical aspects of brain maturation in ASD individuals expands beyond childhood and persists during adulthood.

  8. Absence of age-related prefrontal NAA change in adults with autism spectrum disorders

    PubMed Central

    Aoki, Y; Abe, O; Yahata, N; Kuwabara, H; Natsubori, T; Iwashiro, N; Takano, Y; Inoue, H; Kawakubo, Y; Gonoi, W; Sasaki, H; Murakami, M; Katsura, M; Nippashi, Y; Takao, H; Kunimatsu, A; Matsuzaki, H; Tsuchiya, K J; Kato, N; Kasai, K; Yamasue, H

    2012-01-01

    Atypical trajectory of brain growth in autism spectrum disorders (ASDs) has been recognized as a potential etiology of an atypical course of behavioral development. Numerous neuroimaging studies have focused on childhood to investigate atypical age-related change of brain structure and function, because it is a period of neuron and synapse maturation. Recent studies, however, have shown that the atypical age-related structural change of autistic brain expands beyond childhood and constitutes neural underpinnings for lifelong difficulty to behavioral adaptation. Thus, we examined effects of aging on neurochemical aspects of brain maturation using 3-T proton magnetic resonance spectroscopy (1H-MRS) with single voxel in the medial prefrontal cortex (PFC) in 24 adult men with non-medicated high-functioning ASDs and 25 age-, IQ- and parental-socioeconomic-background-matched men with typical development (TD). Multivariate analyses of covariance demonstrated significantly high N-acetylaspartate (NAA) level in the ASD subjects compared with the TD subjects (F=4.83, P=0.033). The low NAA level showed a significant positive correlation with advanced age in the TD group (r=−0.618, P=0.001), but was not evident among the ASD individuals (r=0.258, P=0.223). Fisher's r-to-z transformation showed a significant difference in the correlations between the ASD and TD groups (Z=−3.23, P=0.001), which indicated that the age–NAA relationship was significantly specific to people with TD. The current 1H-MRS study provided new evidence that atypical age-related change of neurochemical aspects of brain maturation in ASD individuals expands beyond childhood and persists during adulthood. PMID:23092982

  9. Relationship of In Vivo MR Parameters to Histopathological and Molecular Characteristics of Newly Diagnosed, Nonenhancing Lower-Grade Gliomas.

    PubMed

    Luks, Tracy L; McKnight, Tracy Richmond; Jalbert, Llewellyn E; Williams, Aurelia; Neill, Evan; Lobo, Khadjia A; Persson, Anders I; Perry, Arie; Phillips, Joanna J; Molinaro, Annette M; Chang, Susan M; Nelson, Sarah J

    2018-06-05

    The goal of this research was to elucidate the relationship between WHO 2016 molecular classifications of newly diagnosed, nonenhancing lower grade gliomas (LrGG), tissue sample histopathology, and magnetic resonance (MR) parameters derived from diffusion, perfusion, and 1 H spectroscopic imaging from the tissue sample locations and the entire tumor. A total of 135 patients were scanned prior to initial surgery, with tumor cellularity scores obtained from 88 image-guided tissue samples. MR parameters were obtained from corresponding sample locations, and histograms of normalized MR parameters within the T2 fluid-attenuated inversion recovery lesion were analyzed in order to evaluate differences between subgroups. For tissue samples, higher tumor scores were related to increased normalized apparent diffusion coefficient (nADC), lower fractional anisotropy (nFA), lower cerebral blood volume (nCBV), higher choline (nCho), and lower N-acetylaspartate (nNAA). Within the T2 lesion, higher tumor grade was associated with higher nADC, lower nFA, and higher Cho to NAA index. Pathological analysis confirmed that diffusion and metabolic parameters increased and perfusion decreased with tumor cellularity. This information can be used to select targets for tissue sampling and to aid in making decisions about treating residual disease. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  10. Magnetic resonance spectroscopy findings in photosensitive idiopathic generalized epilepsy.

    PubMed

    Aydin-Ozemir, Zeynep; Terzibasioglu, Ege; Altindag, Ebru; Sencer, Serra; Baykan, Betul

    2010-01-01

    Studies investigating the pathophysiology of epileptic photosensitivity indicate variable involvement of particular brain regions. Our aim was to identify metabolic differences between photosensitive idiopathic generalized epilepsy (IGE) patients and nonphotosensitive IGE patients and normal healthy subjects by using Magnetic Resonance Spectroscopy (MRS). Fourteen patients diagnosed with photosensitive IGE were investigated. The control groups consisted of 14 age- and sex-matched healthy volunteers and 14 IGE patients without photosensitivity. MRS measurements of N-acetylaspartate (NAA), choline-containing compounds (Cho), creatine (Cr) were performed in the frontal and occipital cortex and the thalamus bilaterally using a stimulated echo acquisition mode (STEAM) technique with a voxel size of 20 x 20 x 20 mm. The values of the patients with IGE were compared with those of the normal controls and within subgroups according to the clinical variables by appropriate statistical tests. Photosensitive IGE patients showed significantly decreased concentrations of NAA in the right frontal lobe and left thalamus, decreased NAA/Cr ratio in left thalamus and significantly increased concentrations of Cho/Cr ratio in the right frontal lobe and NAA/Cr in the left occipital lobe when compared to normal controls. Furthermore, left occipital NAA concentration increased and left thalamus NAA/Cr ratios were decreased from the IGE patients without photosensitivity but without reaching statistical significance. Our results support previous MR studies suggesting an asymmetrical neuronal dysfunction in favor of the dominant occipital cortex and thalamus in photosensitive IGE patients.

  11. Evaluation of disease progression in INCL by MR spectroscopy

    PubMed Central

    Baker, Eva H; Levin, Sondra W; Zhang, Zhongjian; Mukherjee, Anil B

    2015-01-01

    Objective Infantile neuronal ceroid lipofuscinosis (INCL) is a devastating neurodegenerative storage disease caused by palmitoyl-protein thioesterase-1 deficiency, which impairs degradation of palmitoylated proteins (constituents of ceroid) by lysosomal hydrolases. Consequent lysosomal ceroid accumulation leads to neuronal injury. As part of a pilot study to evaluate treatment benefits of cysteamine bitartrate and N-acetylcysteine, we quantitatively measured brain metabolite levels using magnetic resonance spectroscopy (MRS). Methods A subset of two patients from a larger treatment and follow-up study underwent serial quantitative single-voxel MRS examinations of five anatomical sites. Three echo times were acquired in order to estimate metabolite T2. Measured metabolite levels included correction for partial volume of cerebrospinal fluid. Comparison of INCL patients was made to a reference group composed of asymptomatic and minimally symptomatic Niemann-Pick disease type C patients. Results In INCL patients, N-acetylaspartate (NAA) was abnormally low at all locations upon initial measurement, and further declined throughout the follow-up period. In the cerebrum (affected early in the disease course), choline and myo-inositol were initially elevated and fell during the follow-up period, whereas in the cerebellum and brainstem (affected later), choline and myo-inositol were initially normal and rose subsequently. Interpretation Choline and myo-inositol levels in our patients are consistent with patterns of neuroinflammation observed in two INCL mouse models. Low, persistently declining NAA was expected based on the progressive, irreversible nature of the disease. Progression of metabolite levels in INCL has not been previously quantified; therefore the results of this study serve as a reference for quantitative evaluation of future therapeutic interventions. PMID:26339674

  12. 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.

  13. Structural determinants and cellular environment define processed actin as the sole substrate of the N-terminal acetyltransferase NAA80.

    PubMed

    Goris, Marianne; Magin, Robert S; Foyn, Håvard; Myklebust, Line M; Varland, Sylvia; Ree, Rasmus; Drazic, Adrian; Bhambra, Parminder; Støve, Svein I; Baumann, Markus; Haug, Bengt Erik; Marmorstein, Ronen; Arnesen, Thomas

    2018-04-24

    N-terminal (Nt) acetylation is a major protein modification catalyzed by N-terminal acetyltransferases (NATs). Methionine acidic N termini, including actin, are cotranslationally Nt acetylated by NatB in all eukaryotes, but animal actins containing acidic N termini, are additionally posttranslationally Nt acetylated by NAA80. Actin Nt acetylation was found to regulate cytoskeletal dynamics and motility, thus making NAA80 a potential target for cell migration regulation. In this work, we developed potent and selective bisubstrate inhibitors for NAA80 and determined the crystal structure of NAA80 in complex with such an inhibitor, revealing that NAA80 adopts a fold similar to other NAT enzymes but with a more open substrate binding region. Furthermore, in contrast to most other NATs, the substrate specificity of NAA80 is mainly derived through interactions between the enzyme and the acidic amino acids at positions 2 and 3 of the actin substrate and not residues 1 and 2. A yeast model revealed that ectopic expression of NAA80 in a strain lacking NatB activity partially restored Nt acetylation of NatB substrates, including yeast actin. Thus, NAA80 holds intrinsic capacity to posttranslationally Nt acetylate NatB-type substrates in vivo. In sum, the presence of a dominant cotranslational NatB in all eukaryotes, the specific posttranslational actin methionine removal in animals, and finally, the unique structural features of NAA80 leave only the processed actins as in vivo substrates of NAA80. Together, this study reveals the molecular and cellular basis of NAA80 Nt acetylation and provides a scaffold for development of inhibitors for the regulation of cytoskeletal properties. Copyright © 2018 the Author(s). Published by PNAS.

  14. 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.

  15. Reduced NAA-levels in the NAWM of patients with MS is a feature of progression. A study with quantitative magnetic resonance spectroscopy at 3 Tesla.

    PubMed

    Aboul-Enein, Fahmy; Krssák, Martin; Höftberger, Romana; Prayer, Daniela; Kristoferitsch, Wolfgang

    2010-07-20

    Reduced N-acetyl-aspartate (NAA) levels in magnetic resonance spectroscopy (MRS) may visualize axonal damage even in the normal appearing white matter (NAWM). Demyelination and axonal degeneration are a hallmark in multiple sclerosis (MS). To define the extent of axonal degeneration in the NAWM in the remote from focal lesions in patients with relapsing-remitting (RRMS) and secondary progressive MS (SPMS). 37 patients with clinical definite MS (27 with RRMS, 10 with SPMS) and 8 controls were included. We used 2D (1)H-MR-chemical shift imaging (TR = 1500ms, TE = 135ms, nominal resolution 1ccm) operating at 3Tesla to assess the metabolic pattern in the fronto-parietal NAWM. Ratios of NAA to creatine (Cr) and choline (Cho) and absolute concentrations of the metabolites in the NAWM were measured in each voxel matching exclusively white matter on the anatomical T2 weighted MR images. No significant difference of absolute concentrations for NAA, Cr and Cho or metabolite ratios were found between RRMS and controls. In SPMS, the NAA/Cr ratio and absolute concentrations for NAA and Cr were significantly reduced compared to RRMS and to controls. In our study SPMS patients, but not RRMS patients were characterized by low NAA levels. Reduced NAA-levels in the NAWM of patients with MS is a feature of progression.

  16. 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.

  17. 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.

  18. 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

  19. 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.

  20. N-acetyl-aspartate (NAA) as a correlate of pharmacological treatment in psychiatric disorders: a systematic review.

    PubMed

    Paslakis, Georgios; Träber, Frank; Roberz, Jens; Block, Wolfgang; Jessen, Frank

    2014-10-01

    The amino-acid N-acetyl-aspartate (NAA) is located in neurons and the concentration of NAA correlates with neuronal mitochondrial function. The signal of NAA, as measured with proton magnetic resonance spectroscopy (1H-MRS), is considered to reflect both, neuronal density and integrity of neuronal mitochondria. A reduction of the NAA concentrations has been found in several psychiatric disorders. Newer studies report reversal of decreased NAA concentration with treatment. The objective of this review is to summarize the literature on NAA changes in association with psychopharmacological treatment in psychiatric disorders (affective disorders, obsessive-compulsive disorder, schizophrenia and dementia). The majority of studies identified increased NAA concentrations in response to treatment, while a smaller number of studies did not find this effect. The NAA increase seems to be neither specific for a certain disorder nor for a specific intervention. This suggests that the reduction of NAA may represent an altered functional (metabolic) state of neurons common to different psychiatric disorders and the increase after treatment to indicate functional restoration as one general effect of interventions. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.

  1. 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

  2. [Clinical application of proton magnetic resonance spectroscopy in children with idiopathic epilepsy].

    PubMed

    Shao, Xiao-Li; Zhou, Zhong-Shu; Hong, Wen

    2010-06-01

    This study examined the biochemical metabolism by proton magnetic resonance spectroscopy ('H-MRS) in order to explore the value of 'H-MRS in idiopathic epilepsy in children. Thirty-three children with idiopathic epilepsy (14 cases with history of febrile seizures and 19 cases without) and six normal controls experienced MRI of the skull and brain and single-voxel 'H-MRS examinations of the hippocampi-temporal lobe. The signal intensities of N-acetylaspartate (NAA), eatine+phosphocreatine (Cr), choline-containing compounds (Cho) and lactate (Lac) and the ratios of NAA/ (Cho+Cr) and Lac/Cr were compared between the patients and normal controls. MRI examination showed that only one child with epilepsy had myelin dysplasia. 'H-MRS examination showed that the ratio of NAA/ (Cho+Cr) in the epilepsy group was lower than that in the control group (0.64+/-0.07 vs 0.73+/-0.05; P<0.01). The epileptic children with history of febrile seizures had a more decreased ratio of NAA/ (Cho+Cr) compared with those without the history (0.61+/-0.07 vs 0.66+/-0.06; P<0.05). There were no significant differences in the ratio of Lac/Cr between the epilepsy and the control groups. 'H-MRS may provide early information on brain injury sensitively and non-invasively in children with epilepsy. It may be used for diagnosis and prognosis evaluation of epilepsy.

  3. 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.

  4. 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

  5. Brain metabolite changes in patients with type 2 diabetes and cerebral infarction using proton magnetic resonance spectroscopy.

    PubMed

    Zhang, Min; Sun, Xinhai; Zhang, Zhengjun; Meng, Qiang; Wang, Yuzhong; Chen, Jing; Ma, Xueqin; Geng, Houfa; Sun, Lin

    2014-01-01

    The aim of this study was to investigate the possible brain metabolic alterations in patients with type 2 diabetes mellitus (T2DM) and cerebral infarction (DMCI) using proton magnetic resonance spectroscopy (MRS). Thirty-four patients with T2DM and DMCI were scanned together with 33 patients with nondiabetic cerebral infarction (NDCI) on a 1.5-T MRI/MRS imager. Voxels were placed in the infarcted area and the contralateral normal area in the basal ganglia. N-acetylaspartate (NAA)/creatine (Cr), choline (Cho)/Cr, and lactate (Lac)/Cr ratios were calculated. Cerebral NAA/Cr ratios in the infarcted area were lower than those in the contralateral normal area of the NDCI group. There was a significant decrease in NAA/Cr in the infarcted area of the DMCI group as compared with the infarcted area of the NDCI group. NAA/Cr ratios in the contralateral normal area of DMCI group were lower than those of the NDCI group. Lac/Cr ratios were increased in the infarcted area of both the DMCI group and NDCI group, and Lac/Cr ratios tended to be higher in the infarcted area of the DMCI group than those of the NDCI group. Glycosylated hemoglobin (HbA1c) levels were negatively correlated with NAA/Cr ratios. The study suggested that the metabolite changes were different between DMCI patients and NDCI patients, which may provide important information in the treatment of DMCI.

  6. Spectroscopic Axonal Damage of the Right Locus Coeruleus Relates to Selective Attention Impairment in Early Stage Relapsing-Remitting Multiple Sclerosis

    ERIC Educational Resources Information Center

    Gadea, Marien; Martinez-Bisbal, M. Carmen; Marti-Bonmati, Luis; Espert, Raul; Casanova, Bonaventura; Coret, Francisco; Celda, Bernardo

    2004-01-01

    Lower levels of N-acetylaspartate (NAA), a marker of axonal damage, have been found in the normal-appearing white matter (NAWM) of relapsing-remitting multiple sclerosis (RRMS) patients with low physical disability. However, its relation to the clinical status of these patients remains unclear. We explored the association between NAA levels…

  7. 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

  8. 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.

  9. Imaging Intelligence with Proton Magnetic Resonance Spectroscopy

    ERIC Educational Resources Information Center

    Jung, Rex E.; Gasparovic, Charles; Chavez, Robert S.; Caprihan, Arvind; Barrow, Ranee; Yeo, Ronald A.

    2009-01-01

    Proton magnetic resonance spectroscopy ([to the first power]H-MRS) is a technique for the assay of brain neurochemistry "in vivo." N-acetylaspartate (NAA), the most prominent metabolite visible within the [to the first power]H-MRS spectrum, is found primarily within neurons. The current study was designed to further elucidate NAA-cognition…

  10. Lower Choline and Myo-Inositol in Temporo-Parietal Cortex Is Associated With Apathy in Amnestic MCI.

    PubMed

    Tumati, Shankar; Opmeer, Esther M; Marsman, Jan-Bernard C; Martens, Sander; Reesink, Fransje E; De Deyn, Peter P; Aleman, André

    2018-01-01

    Apathy is a common symptom in patients with amnestic mild cognitive impairment (aMCI) and is associated with an increased risk of progression to Alzheimer's disease (AD). The neural substrates underlying apathy in aMCI may involve multiple brain regions, including the anterior cingulate cortex and the temporo-parietal region. Here we investigated neurometabolites in brain regions that may underlie apathy in aMCI patients using proton magnetic resonance spectroscopy ( 1 H-MRS). Twenty-eight aMCI patients with varying degrees of apathy and 20 matched controls underwent 1 H-MRS. Spectra were acquired from single voxels in the posterior cingulate cortex (PCC), dorsal anterior cingulate cortex (DACC), right dorsolateral prefrontal cortex (DLPFC), and right temporo-parietal cortex (TPC). Apathy was measured with the Apathy Evaluation Scale (AES). Spearman partial correlations between metabolite concentrations in each region and severity of apathy were determined. Additionally, analyses of covariance (ANCOVA) were performed to determine whether metabolite changes differed between patients with or without clinically-diagnosed apathy. The degree of apathy was found to be negatively correlated with choline and myo-inositol (mI) in the TPC. Additional exploratory analyses suggested that N-acetylaspartate (NAA)/mI ratio was reduced in aMCI without clinical apathy but not in aMCI with clinical apathy. In the DACC, glutamate and glutamine (Glx) levels tended to be higher in the aMCI with apathy group compared to controls and reduced in association with depression scores. In conclusion, apathy in aMCI patients was associated with neurometabolite changes indicative of altered membranal integrity and glial function in the right TPC. Findings also indicated that in a clinically-diagnosed aMCI cohort, apathy symptoms may be suggestive of neural changes that are distinct from aMCI without apathy.

  11. A multi-matrix HILIC-MS/MS method for the quantitation of endogenous small molecule neurological biomarker N-acetyl aspartic acid (NAA).

    PubMed

    Sangaraju, Dewakar; Shahidi-Latham, Sheerin K; Burgess, Braydon L; Dean, Brian; Ding, Xiao

    2017-06-05

    A multi-matrix hydrophilic interaction liquid chromatography tandem mass spectrometric method (HILIC-MS/MS) was developed for the quantitation of N-Acetyl Aspartic acid (NAA) using stable isotope labeled internal standard, D3-NAA in various biological matrices such as human plasma, human CSF, mouse plasma, brain and spinal cord. A high throughput 96-well plate format supported liquid extraction (SLE) procedure was developed and used for sample preparation. Mass spectrometric analysis of NAA was performed using selected reaction monitoring transitions in positive electrospray ionization mode. As NAA is endogenously present, a surrogate matrix approach was used for quantitation of NAA and the method was qualified over linear calibration curve range of 0.01-10μg/mL. Intra and inter assay precision indicated by percent relative standard deviation (%RSD) was less than 7.1% for low, medium, medium high and high QCs. The accuracy of the method ranged from 92.6-107.0% of nominal concentration for within-run and between-run for the same QCs. Extraction recovery of NAA and D3-NAA was greater than 76%. Stability of NAA was established in the above biological matrices under bench top (RT, 5h), freeze thaw (-20±10°C, 3 cycles) and moues/human plasma sample collection (Wet ice, RT) conditions. HILIC-MS/MS method was then used to quantify and compare the NAA levels in human plasma and CSF of ALS patients versus control human subjects. NAA CSF levels in control human subjects (73.3±31.0ng/mL,N=10) were found to be slightly higher than ALS patients (46.1±22.6ng/mL, N=10) (P=0.04). No differences were observed in NAA plasma levels in human control subjects (49.7±13.8ng/mL,N=9) as compared to ALS patients (49.6±8.1ng/mL, N=10) (P=0.983). NAA endogenous concentrations in mouse plasma, brain and spinal cord were found to be 243.8±56.8ng/mL (N=6), 1029.8±115.2μg/g tissue weight (N=5) and 487.6±178.4μg/g tissue weight (N=5) respectively. Copyright © 2017 Elsevier B.V. All

  12. 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.

  13. 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.

  14. Brain metabolites in autonomic regulatory insular sites in heart failure.

    PubMed

    Woo, Mary A; Yadav, Santosh K; Macey, Paul M; Fonarow, Gregg C; Harper, Ronald M; Kumar, Rajesh

    2014-11-15

    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 2.02 ppm, Cr at 3.02 ppm, Cho at 3.2 ppm, and MI at 3.56 ppm were assigned, peak areas were calculated, and metabolites were 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. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. 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

  16. 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

  17. 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.

  18. [Impacts of electroacupuncture on left hippocampus NAA/Cr for patients of Uygur and Han nationality with mild cognitive impairment].

    PubMed

    Liu, Zhi-Yan; Guo, Hui; Zhang, Xiao-Lin; Liu, Juan; Qu, Hong-Yan; Peng, Wei; Bao, Yi-Mei; Yin, Li-Li; Song, Yi-Xing

    2011-09-01

    To observe the clinical efficacy of electroacupuncture (EA) on mild cognitive impairment (MCI) for patients of Uygur and Han nationality and explore the national diversity among the patients with MCI. Twenty-five cases were divided into Han nationality group (15 cases) and Uygur nationality group (10 cases) according to patient's nationality. In either group, EA was applied to Baihui (GV 20), Fengchi (GB 20), Xuanzhong (GB 39), Fuliu (KI 7), Sanyinjiao (SP 6) and Taixi (KI 3), once per day, 15 treatments made one session and there were 5 days at the interval among the sessions. Totally, 3 sessions of treatment were required. The proton magnetic resonance spectroscopy (1H-MRS) was used to observe the changes in the ratio of N-acetylaspartate and creatine (NAA/Cr) on the left hippocampus for the patients in two groups before and after treatment as well as the changes in the results of the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) separately. NAA/Cr in Uygur nationality group was higher than that in Han nationality group before treatment (1.659 +/- 0.418 vs 1.137 +/- 0.190, P < 0.05). After treatment, MMSE and MoCA scores all increased apparently as compared with those before treatment in two groups (P < 0.05, P < 0.01), and NAA/Cr on the left hippocampus in either group was up-regulated as compared with that before treatment (both P < 0.01). EA can improve the overall cognitive function for the patients with MCI. There is the national diversity in the partial brain metabolite level between Uygur patients and Han patients with MCI.

  19. Brain abscess mimicking brain metastasis in breast cancer.

    PubMed

    Khullar, Pooja; Datta, Niloy R; Wahi, Inderjeet Kaur; Kataria, Sabeena

    2016-03-01

    61 year old female presented with chief complaints of headache for 30 days, fever for 10 days, altered behavior for 10 days and convulsion for 2 days. She was diagnosed and treated as a case of carcinoma of left breast 5 years ago. MRI brain showed a lobulated lesion in the left frontal lobe. She came to our hospital for whole brain radiation as a diagnosed case of carcinoma of breast with brain metastasis. Review of MRI brain scan, revealed metastasis or query infective pathology. MR spectroscopy of the lesion revealed choline: creatinine and choline: NAA (N-Acetylaspartate) ratios of ∼1.6 and 1.5 respectively with the presence of lactate within the lesion suggestive of infective pathology. She underwent left fronto temporal craniotomy and evacuation of abscess and subdural empyema. Gram stain showed gram positive cocci. After 1 month of evacuation and treatment she was fine. This case suggested a note of caution in every case of a rapidly evolving space-occupying lesion independent of the patient's previous history. Copyright © 2015 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

  20. 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.

  1. 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

  2. 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.

  3. 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.

  4. Serial MR Spectroscopy Reveals a Direct Metabolic Effect of Cediranib in Glioblastoma

    PubMed Central

    Kim, Heisoog; Catana, Ciprian; Ratai, Eva-Maria; Andronesi, Ovidiu C.; Jennings, D.; Batchelor, Tracy T.; Jain, Rakesh K.; Sorensen, A. Gregory

    2011-01-01

    Proton magnetic resonance spectroscopy (1H-MRS) is increasingly used in clinical studies of brain tumor to provide information about tissue metabolic profiles. In this study, we evaluated changes in the levels of metabolites predominant in recurrent glioblastoma (rGBM), to characterize the response of rGBM to anti-angiogenic therapy. We examined thirty-one rGBM patients treated with daily doses of cediranib, acquiring serial chemical shift imaging data at specific time points during the treatment regimen. We defined spectra from three regions of interest (ROIs)—enhancing tumor (ET), peritumoral tissue (PT), and normal tissue on the contralateral side (cNT)—in post-contrast T1-weighted images, and normalized the concentrations of N-acetylaspartate (NAA) and choline (Cho) in each ROI to the concentration of creatine in cNT (norCre). We analyzed the ratios of these normalized metabolites (i.e., NAA/Cho, NAA/norCre, and Cho/norCre) by averaging all patients and categorizing two different survival groups. Relative to pre-treatment values, NAA/Cho in ET was unchanged through day 28. However, after day 28, NAA/Cho significantly increased in relation to a significant increase in NAA/norCre and a decrease in Cho/norCre; interestingly, the observed trend was reversed after day 56, consistent with the clinical course of GBM recurrence. Notably, ROC analysis indicated that NAA/Cho in tumor shows a high prediction to 6-month overall survival. These metabolic changes in these rGBM patients strongly suggest a direct metabolic effect of cediranib, and might also reflect an anti-tumor response to anti-angiogenic treatment during the first two months of treatment. Further study is needed to confirm these findings. PMID:21507932

  5. Longitudinal investigation of neuroinflammation and metabolite profiles in the APPswe ×PS1Δe9 transgenic mouse model of Alzheimer's disease.

    PubMed

    Chaney, Aisling; Bauer, Martin; Bochicchio, Daniela; Smigova, Alison; Kassiou, Michael; Davies, Karen E; Williams, Steve R; Boutin, Herve

    2018-02-01

    There is increasing evidence linking neuroinflammation to many neurological disorders including Alzheimer's disease (AD); however, its exact contribution to disease manifestation and/or progression is poorly understood. Therefore, there is a need to investigate neuroinflammation in both health and disease. Here, we investigate cognitive decline, neuroinflammatory and other pathophysiological changes in the APP swe ×PS1 Δe9 transgenic mouse model of AD. Transgenic (TG) mice were compared to C57BL/6 wild type (WT) mice at 6, 12 and 18 months of age. Neuroinflammation was investigated by [ 18 F]DPA-714 positron emission tomography and myo-inositol levels using 1 H magnetic resonance spectroscopy (MRS) in vivo. Neuronal and cellular dysfunction was investigated by looking at N-acetylaspartate (NAA), choline-containing compounds, taurine and glutamate also using MRS. Cognitive decline was first observed at 12 m of age in the TG mice as assessed by working memory tests . A significant increase in [ 18 F]DPA-714 uptake was seen in the hippocampus and cortex of 18 m-old TG mice when compared to age-matched WT mice and 6 m-old TG mice. No overall effect of gene was seen on metabolite levels; however, a significant reduction in NAA was observed in 18 m-old TG mice when compared to WT. In addition, age resulted in a decrease in glutamate and an increase in choline levels. Therefore, we can conclude that increased neuroinflammation and cognitive decline are observed in TG animals, whereas NAA alterations occurring with age are exacerbated in the TG mice. These results support the role of neuroinflammation and metabolite alteration in AD and in ageing. © 2017 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.

  6. 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.

  7. 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

  8. 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.

  9. Adding Sarcosine to Antipsychotic Treatment in Patients with Stable Schizophrenia Changes the Concentrations of Neuronal and Glial Metabolites in the Left Dorsolateral Prefrontal Cortex.

    PubMed

    Strzelecki, Dominik; Podgórski, Michał; Kałużyńska, Olga; Stefańczyk, Ludomir; Kotlicka-Antczak, Magdalena; Gmitrowicz, Agnieszka; Grzelak, Piotr

    2015-10-15

    The glutamatergic system is a key point in pathogenesis of schizophrenia. Sarcosine (N-methylglycine) is an exogenous amino acid that acts as a glycine transporter inhibitor. It modulates glutamatergic transmission by increasing glycine concentration around NMDA (N-methyl-d-aspartate) receptors. In patients with schizophrenia, the function of the glutamatergic system in the prefrontal cortex is impaired, which may promote negative and cognitive symptoms. Proton nuclear magnetic resonance (¹H-NMR) spectroscopy is a non-invasive imaging method enabling the evaluation of brain metabolite concentration, which can be applied to assess pharmacologically induced changes. The aim of the study was to evaluate the influence of a six-month course of sarcosine therapy on the concentration of metabolites (NAA, N-acetylaspartate; Glx, complex of glutamate, glutamine and γ-aminobutyric acid (GABA); mI, myo-inositol; Cr, creatine; Cho, choline) in the left dorso-lateral prefrontal cortex (DLPFC) in patients with stable schizophrenia. Fifty patients with schizophrenia, treated with constant antipsychotics doses, in stable clinical condition were randomly assigned to administration of sarcosine (25 patients) or placebo (25 patients) for six months. Metabolite concentrations in DLPFC were assessed with 1.5 Tesla ¹H-NMR spectroscopy. Clinical symptoms were evaluated with the Positive and Negative Syndrome Scale (PANSS). The first spectroscopy revealed no differences in metabolite concentrations between groups. After six months, NAA/Cho, mI/Cr and mI/Cho ratios in the left DLPFC were significantly higher in the sarcosine than the placebo group. In the sarcosine group, NAA/Cr, NAA/Cho, mI/Cr, mI/Cho ratios also significantly increased compared to baseline values. In the placebo group, only the NAA/Cr ratio increased. The addition of sarcosine to antipsychotic therapy for six months increased markers of neurons viability (NAA) and neurogilal activity (mI) with simultaneous improvement

  10. 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.

  11. 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

  12. Diffusion tensor imaging and 1H-MRS study on radiation-induced brain injury after nasopharyngeal carcinoma radiotherapy.

    PubMed

    Wang, H-Z; Qiu, S-J; Lv, X-F; Wang, Y-Y; Liang, Y; Xiong, W-F; Ouyang, Z-B

    2012-04-01

    To investigate the metabolic characteristics of the temporal lobes following radiation therapy for nasopharyngeal carcinoma using diffusion tensor imaging (DTI) and proton magnetic resonance spectroscopy ((1)H-MRS). DTI and (1)H-MRS were performed in 48 patients after radiotherapy for nasopharyngeal carcinoma and in 24 healthy, age-matched controls. All patients and controls had normal findings on conventional MRI. Apparent diffusion coefficient (ADC), fractional anisotropy (FA), three eigenvalues λ1, λ2, λ3, N-acetylaspartic acid (NAA)/choline (Cho), NAA/creatinine (Cr), and Cho/Cr were measured in both temporal lobes. Patients were divided into three groups according to time after completion of radiotherapy: group 1, less than 6 months; group 2, 6-12 months; group 3, more than 12 months. Mean values for each parameter were compared using one-way analysis of variance (ANOVA). Mean FA in group 1 was significantly lower compared to group 3 and the control group (p < 0.05). Group-wise comparisons of apparent diffusion coefficient (ADC) values among all the groups were not significantly different. Eigenvalue λ1 was significantly lower in groups 1 and 3 compared to the control group (p < 0.05). NAA/Cho and NAA/Cr were significantly lower in each group compared to the control group (p < 0.01 for both). The decrease in NAA/Cho was greatest in group 1. There were no significant between-group differences regarding Cho/Cr. A combination of DTI and (1)H-MRS can be used to detect radiation-induced brain injury, in patients treated for nasopharyngeal carcinoma. Copyright © 2011 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

  13. 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

  14. 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.

  15. Depletion of histone N-terminal-acetyltransferase Naa40 induces p53-independent apoptosis in colorectal cancer cells via the mitochondrial pathway.

    PubMed

    Pavlou, Demetria; Kirmizis, Antonis

    2016-03-01

    Protein N-terminal acetylation is an abundant post-translational modification in eukaryotes implicated in various fundamental cellular and biochemical processes. This modification is catalysed by evolutionarily conserved N-terminal acetyltransferases (NATs) whose deregulation has been linked to cancer development and thus, are emerging as useful diagnostic and therapeutic targets. Naa40 is a highly selective NAT that acetylates the amino-termini of histones H4 and H2A and acts as a sensor of cell growth in yeast. In the present study, we examine the role of Naa40 in cancer cell survival. We demonstrate that depletion of Naa40 in HCT116 and HT-29 colorectal cancer cells decreases cell survival by enhancing apoptosis, whereas Naa40 reduction in non-cancerous mouse embryonic fibroblasts has no effect on cell viability. Specifically, Naa40 knockdown in colon cancer cells activates the mitochondrial caspase-9-mediated apoptotic cascade. Consistent with this, we show that caspase-9 activation is required for the induced apoptosis because treatment of cells with an irreversible caspase-9 inhibitor impedes apoptosis when Naa40 is depleted. Furthermore, the effect of Naa40-depletion on cell-death is mediated through a p53-independent mechanism since p53-null HCT116 cells still undergo apoptosis upon reduction of the acetyltransferase. Altogether, these findings reveal an anti-apoptotic role for Naa40 and exhibit its potential as a therapeutic target in colorectal cancers.

  16. Altered chemical metabolites in the amygdala-hippocampus region contribute to autistic symptoms of autism spectrum disorders.

    PubMed

    Endo, Taro; Shioiri, Toshiki; Kitamura, Hideaki; Kimura, Teruo; Endo, Sumio; Masuzawa, Naio; Someya, Toshiyuki

    2007-11-01

    Although several previous studies have been conducted, the neural basis of autism spectrum disorder (ASD) is poorly understood. The objective of the present study was to determine whether individuals with ASD have altered brain chemical metabolites and whether such alterations are related to their autistic symptoms. N-acetylaspartate (NAA)/creatine (Cr) and choline/Cr ratios in the right medial temporal lobe (MTL), medial prefrontal cortex, and cerebellar vermis were measured in 38 individuals with ASD (mean age = 12.9 years), including 12 with autism, 15 with Asperger's Disorder, and 11 with pervasive developmental disorder not otherwise specified (PDD-NOS), and 16 matched healthy control subjects (mean age = 11.5 years) with proton magnetic resonance spectroscopy. Autistic symptoms were assessed by the Childhood Autistic Rating Scale-Tokyo Version. There was a significant group difference for NAA/Cr ratio in the right MTL between the autism, Asperger's Disorder, PDD-NOS, and control groups (p < .001), and the autism group had a significantly lower NAA/Cr ratio compared with the PDD-NOS (p < .001) and control (p < .001) groups. In the ASD group, there was a significant negative correlation between NAA/Cr ratio in the right MTL and their Childhood Autistic Rating Scale-Tokyo Version total scores (r = -.44, p = .01) and subscales of emotional response (r = -.38, p = .02) and listening response (r = -.54, p = .001). The results of the present study suggest that subjects with ASD have abnormalities of neural integrity in the amygdala-hippocampus region that are related to their severity and social impairments.

  17. Effects of fluoxetine on the amygdala and the hippocampus after administration of a single prolonged stress to male Wistar rates: In vivo proton magnetic resonance spectroscopy findings.

    PubMed

    Han, Fang; Xiao, Bing; Wen, Lili; Shi, Yuxiu

    2015-05-30

    Posttraumatic stress disorder (PTSD) is an anxiety- and memory-based disorder. The hippocampus and amygdala are key areas in mood regulation. Fluoxetine was found to improve the anxiety-related symptoms of PTSD patients. However, little work has directly examined the effects of fluoxetine on the hippocampus and the amygdala. In the present study, male Wistar rats received fluoxetine or vehicle after exposure to a single prolonged stress (SPS), an animal model of PTSD. In vivo proton magnetic resonance spectroscopy ((1)H-MRS) was performed -1, 1, 4, 7 and 14 days after SPS to examine the effects of fluoxetine on neurometabolite changes in amygdala, hippocampus and thalamus. SPS increased the N-acetylaspartate (NAA)/creatine (Cr) and choline moieties (Cho)/Cr ratios in the bilateral amygdala on day 4, decreased the NAA/Cr ratio in the left hippocampus on day 1, and increased both ratios in the right hippocampus on day 14. But no significant change was found in the thalamus. Fluoxetine treatment corrected the SPS increases in the NAA/Cr and Cho/Cr levels in the amygdala on day 4 and in the hippocampus on day 14, but it failed to normalise SPS-associated decreases in NAA/Cr levels in the left hippocampus on day 1. These results suggested that metabolic abnormalities in the amygdala and the hippocampus were involved in SPS, and different effects of fluoxetine in correcting SPS-induced neurometabolite changes among the three areas. These findings have implications for fluoxetine treatment in PTSD. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  18. Effect of occupational manganese exposure on the central nervous system of welders: 1H magnetic resonance spectroscopy and MRI findings.

    PubMed

    Kim, Eun A; Cheong, Hae-Kwan; Choi, Dae Seob; Sakong, Joon; Ryoo, Jae Wook; Park, Injeong; Kang, Dong Mug

    2007-03-01

    This study investigated the relationship between long-term occupational manganese (Mn) exposure on the regional Mn concentration in the brain, neuronal loss, and neurobehavioral effects on welders. 1H MRS of the basal ganglia (BG) was performed on 20 male welders and 10 age- and gender-matched, non-office, control workers in a shipyard to assess the metabolic change, and the N-acetylaspartate (NAA)/creatine (Cr), choline (Cho)/Cr and NAA/Cho ratios, by the level of Mn exposure. We also assessed the signal intensity of T1-weighted image of magnetic resonance imaging (MRI) on globus pallidus (GP) compared to that of the frontal white matter (pallidal index, PI). The welders had significantly higher signal intensity than the controls. PI showed a significant dose-response relationship with cumulative exposure index (CEI) (r=0.54, p=0.002). CEI and PI showed different relationships with NAA/Cr according to smoking status, and the correlation was evident only in non-smokers (r=-0.73 and -0.57, respectively). There were no significant differences between the welders and the controls in NAA/Cr, Cho/Cr, and NAA/Cho ratios obtained from BG. CEI was positively correlated with simple reaction time. PI was positively correlated with mean sway (MSWAY), sway area (SWAYA), and sway intensity (SWAYI), and negatively correlated with maximum frequency (MAXF). After categorizing the subjects into two groups according to NAA/Cr ratio level, the low NAA/Cr ratio group showed significantly lower score on digit span backward and significantly higher score on MSWAY, SWAYA and SWAYI in regression analysis than the high NAA/Cr ratio group. We speculated that the NAA/Cr ratio of MRS in BG seems to reflect the cumulative effect of Mn exposure on the human brain. Due to uneven distribution of smoking among the welders and the controls, in addition to the small number of subjects in our study, our findings are needed further studies with a larger number of subjects.

  19. 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.

  20. 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

  1. 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

  2. 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

  3. 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.

  4. 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.

  5. 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.

  6. The relationship between Cho/NAA and glioma metabolism: implementation for margin delineation of cerebral gliomas.

    PubMed

    Guo, Jun; Yao, Chengjun; Chen, Hong; Zhuang, Dongxiao; Tang, Weijun; Ren, Guang; Wang, Yin; Wu, Jinsong; Huang, Fengping; Zhou, Liangfu

    2012-08-01

    The marginal delineation of gliomas cannot be defined by conventional imaging due to their infiltrative growth pattern. Here we investigate the relationship between changes in glioma metabolism by proton magnetic resonance spectroscopic imaging ((1)H-MRSI) and histopathological findings in order to determine an optimal threshold value of choline/N-acetyl-aspartate (Cho/NAA) that can be used to define the extent of glioma spread. Eighteen patients with different grades of glioma were examined using (1)H-MRSI. Needle biopsies were performed under the guidance of neuronavigation prior to craniotomy. Intraoperative magnetic resonance imaging (MRI) was performed to evaluate the accuracy of sampling. Haematoxylin and eosin, and immunohistochemical staining with IDH1, MIB-1, p53, CD34 and glial fibrillary acidic protein (GFAP) antibodies were performed on all samples. Logistic regression analysis was used to determine the relationship between Cho/NAA and MIB-1, p53, CD34, and the degree of tumour infiltration. The clinical threshold ratio distinguishing tumour tissue in high-grade (grades III and IV) glioma (HGG) and low-grade (grade II) glioma (LGG) was calculated. In HGG, higher Cho/NAA ratios were associated with a greater probability of higher MIB-1 counts, stronger CD34 expression, and tumour infiltration. Ratio threshold values of 0.5, 1.0, 1.5 and 2.0 appeared to predict the specimens containing the tumour with respective probabilities of 0.38, 0.60, 0.79, 0.90 in HGG and 0.16, 0.39, 0.67, 0.87 in LGG. HGG and LGG exhibit different spectroscopic patterns. Using (1)H-MRSI to guide the extent of resection has the potential to improve the clinical outcome of glioma surgery.

  7. 3-Dimensional magnetic resonance spectroscopic imaging at 3 Tesla for early response assessment of glioblastoma patients during external beam radiation therapy.

    PubMed

    Muruganandham, Manickam; Clerkin, Patrick P; Smith, Brian J; Anderson, Carryn M; Morris, Ann; Capizzano, Aristides A; Magnotta, Vincent; McGuire, Sarah M; Smith, Mark C; Bayouth, John E; Buatti, John M

    2014-09-01

    To evaluate the utility of 3-dimensional magnetic resonance (3D-MR) proton spectroscopic imaging for treatment planning and its implications for early response assessment in glioblastoma multiforme. Eighteen patients with newly diagnosed, histologically confirmed glioblastoma had 3D-MR proton spectroscopic imaging (MRSI) along with T2 and T1 gadolinium-enhanced MR images at simulation and at boost treatment planning after 17 to 20 fractions of radiation therapy. All patients received standard radiation therapy (RT) with concurrent temozolomide followed by adjuvant temozolomide. Imaging for response assessment consisted of MR scans every 2 months. Progression-free survival was defined by the criteria of MacDonald et al. MRSI images obtained at initial simulation were analyzed for choline/N-acetylaspartate ratios (Cho/NAA) on a voxel-by-voxel basis with abnormal activity defined as Cho/NAA ≥2. These images were compared on anatomically matched MRSI data collected after 3 weeks of RT. Changes in Cho/NAA between pretherapy and third-week RT scans were tested using Wilcoxon matched-pairs signed rank tests and correlated with progression-free survival, radiation dose and location of recurrence using Cox proportional hazards regression. After a median follow-up time of 8.6 months, 50% of patients had experienced progression based on imaging. Patients with a decreased or stable mean or median Cho/NAA values had less risk of progression (P<.01). Patients with an increase in mean or median Cho/NAA values at the third-week RT scan had a significantly greater chance of early progression (P<.01). An increased Cho/NAA at the third-week MRSI scan carried a hazard ratio of 2.72 (95% confidence interval, 1.10-6.71; P=.03). Most patients received the prescription dose of RT to the Cho/NAA ≥2 volume, where recurrence most often occurred. Change in mean and median Cho/NAA detected at 3 weeks was a significant predictor of early progression. The potential impact for risk

  8. 3D-MR Spectroscopic Imaging at 3Tesla for Early Response Assessment of Glioblastoma Patients during External Beam Radiation Therapy

    PubMed Central

    Muruganandham, Manickam; Clerkin, Patrick P; Smith, Brian J; Anderson, Carryn M; Morris, Ann; Capizzano, Aristides A; Magnotta, Vincent; McGuire, Sarah M; Smith, Mark C; Bayouth, John E; Buatti, John M

    2014-01-01

    Purpose To evaluate the utility of 3D-MR proton spectroscopic imaging for treatment planning and its implications for early response assessment in glioblastoma multiforme. Methods and Materials Eighteen patients with newly diagnosed, histologically confirmed glioblastoma had 3D-MR proton spectroscopic imaging (MRSI) along with T2 and T1 gadolinium enhanced MR images at simulation and at boost treatment planning after 17-20 fractions of radiotherapy. All patients received standard radiotherapy with temozolomide and follow-up with every two month MR scans. Progression free survival was defined using MacDonald criteria. MRSI images obtained at initial simulation were analyzed for choline / N-acetylaspartate ratios (Cho/NAA) on a voxel by voxel basis with abnormal activity defined as Cho/NAA ≥ 2. These images were compared on anatomically matched MRSI data collected after 3 weeks of radiotherapy. Changes in Cho/NAA between pre-therapy and 3rd week RT scans were tested using Wilcoxon matched-pairs signed rank tests and correlated with progression free survival, radiation dose and location of recurrence using Cox proportional hazards regression. Results After 8.6 months (median follow-up), 50% of patients had progressed based on imaging. Patients with a decreased or stable mean or median Cho/NAA values had less risk of progression (p< 0.01). Patients with an increase in mean or median Cho/NAA values at the 3rd week RT scan had a significantly greater chance of early progression (p <0.01). An increased Cho/NAA at the 3rd week MRSI scan carried a hazard ratio of 2.72 (95% confidence interval 1.10-6.71, p= 0.03). Most patients received the prescription dose of RT to the Cho/NAA ≥ 2 volume, which was where recurrence most often occurred. Conclusion Change in mean and median Cho/NAA detected at 3 weeks was a significant predictor of early progression. The potential impact for risk-adaptive therapy based on early spectroscopic findings is suggested. PMID:24986746

  9. 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.

  10. 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.

  11. 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

  12. Manifestations of early brain recovery associated with abstinence from alcoholism.

    PubMed

    Bartsch, Andreas J; Homola, György; Biller, Armin; Smith, Stephen M; Weijers, Heinz-Gerd; Wiesbeck, Gerhard A; Jenkinson, Mark; De Stefano, Nicola; Solymosi, László; Bendszus, Martin

    2007-01-01

    Chronic alcohol abuse results in morphological, metabolic, and functional brain damage which may, to some extent, be reversible with early effects upon abstinence. Although morphometric, spectroscopic, and neuropsychological indicators of cerebral regeneration have been described previously, the overall amount and spatial preference of early brain recovery attained by abstinence and its associations with other indicators of regeneration are not well established. We investigated global and local brain volume changes in a longitudinal two-timepoint study with T1-weighted MRI at admission and after short-term (6-7 weeks) sobriety follow-up in 15 uncomplicated, recently detoxified alcoholics. Volumetric brain gain was related to metabolic and neuropsychological recovery. On admission and after short-term abstinence, structural image evaluation using normalization of atrophy (SIENA), its voxelwise statistical extension to multiple subjects, proton MR spectroscopy (1H-MRS), and neuropsychological tests were applied. Upon short-term sobriety, 1H-MRS levels of cerebellar choline and frontomesial N-acetylaspartate (NAA) were significantly augmented. Automatically detected global brain volume gain amounted to nearly two per cent on average and was spatially significant around the superior vermis, perimesencephalic, periventricular and frontal brain edges. It correlated positively with the percentages of cerebellar and frontomesial choline increase, as detected by 1H-MRS. Moreover, frontomesial NAA gains were associated with improved performance on the d2-test of attention. In 10 age- and gender-matched healthy control subjects, no significant brain volume or metabolite changes were observed. Although cerebral osmotic regulations may occur initially upon sobriety, significant increases of cerebellar choline and frontomesial NAA levels detected at stable brain water integrals and creatine concentrations, serum electrolytes and red blood cell indices in our patient sample

  13. Comparison of LCModel and SAGE in Analysis of Brain Metabolite Concentrations-A study of Patients with Mild Cognitive Impairment.

    PubMed

    Shih, Chiu-Ming; Lai, Jui-Jen; Chang, Chin-Ching; Chen, Cheng-Sheng; Yeh, Yi-Chun; Jaw, Twei-Shiun; Hsu, Jui-Sheng; Li, Chun-Wei

    2017-03-15

    The purpose of this study was to compare brain metabolite concentration ratios determined by LCModel and Spectroscopy Analysis by General Electric (SAGE) quantitative methods to elucidate the advantages and disadvantages of each method. A total of 10 healthy volunteers and 10 patients with mild cognitive impairment (MCI) were recruited in this study. A point-resolved spectroscopy (PRESS) sequence was used to obtain the brain magnetic resonance spectroscopy (MRS) spectra of the volunteers and patients, as well as the General Electric (GE) MRS-HD-sphere phantom. The brain metabolite concentration ratios were estimated based on the peak area obtained from both LCModel and SAGE software. Three brain regions were sampled for each volunteer or patient, and 20 replicates were acquired at different times for the phantom analysis. The metabolite ratios of the GE phantom were estimated to be myo-inositol (mI)/creatine (Cr): 0.70 ± 0.01, choline (Cho)/Cr: 0.37 ± 0.00, N-acetylaspartate (NAA)/Cr: 1.26 ± 0.02, and NAA/mI: 1.81 ± 0.04 by LCModel, and mI/Cr: 0.88 ± 0.15, Cho/Cr: 0.35 ± 0.01, NAA/Cr: 1.33 ± 0.03, and NAA/mI: 1.55 ± 0.26 by SAGE. In the healthy volunteers and MCI patients, the ratios of mI/Cr and Cho/Cr estimated by LCModel were higher than those estimated by SAGE. In contrast, the ratio of NAA/Cr estimated by LCModel was lower than that estimated by SAGE. Both methods were acceptable in estimating brain metabolite concentration ratios. However, LCModel was marginally more accurate than SAGE because of its full automation, basis set, and user independency.

  14. Simulating the Effect of Spectroscopic MRI as a Metric for Radiation Therapy Planning in Patients with Glioblastoma

    PubMed Central

    Cordova, J. Scott; Kandula, Shravan; Gurbani, Saumya; Zhong, Jim; Tejani, Mital; Kayode, Oluwatosin; Patel, Kirtesh; Prabhu, Roshan; Schreibmann, Eduard; Crocker, Ian; Holder, Chad A.; Shim, Hyunsuk; Shu, Hui-Kuo

    2017-01-01

    Due to glioblastoma’s infiltrative nature, an optimal radiation therapy (RT) plan requires targeting infiltration not identified by anatomical magnetic resonance imaging (MRI). Here, high-resolution, whole-brain spectroscopic MRI (sMRI) is used to describe tumor infiltration alongside anatomical MRI and simulate the degree to which it modifies RT target planning. In 11 patients with glioblastoma, data from preRT sMRI scans were processed to give high-resolution, whole-brain metabolite maps normalized by contralateral white matter. Maps depicting choline to N-Acetylaspartate (Cho/NAA) ratios were registered to contrast-enhanced T1-weighted RT planning MRI for each patient. Volumes depicting metabolic abnormalities (1.5−, 1.75−, and 2.0-fold increases in Cho/NAA ratios) were compared with conventional target volumes and contrast-enhancing tumor at recurrence. sMRI-modified RT plans were generated to evaluate target volume coverage and organ-at-risk dose constraints. Conventional clinical target volumes and Cho/NAA abnormalities identified significantly different regions of microscopic infiltration with substantial Cho/NAA abnormalities falling outside of the conventional 60 Gy isodose line (41.1, 22.2, and 12.7 cm3, respectively). Clinical target volumes using Cho/NAA thresholds exhibited significantly higher coverage of contrast enhancement at recurrence on average (92.4%, 90.5%, and 88.6%, respectively) than conventional plans (82.5%). sMRI-based plans targeting tumor infiltration met planning objectives in all cases with no significant change in target coverage. In 2 cases, the sMRI-modified plan exhibited better coverage of contrast-enhancing tumor at recurrence than the original plan. Integration of the high-resolution, whole-brain sMRI into RT planning is feasible, resulting in RT target volumes that can effectively target tumor infiltration while adhering to conventional constraints. PMID:28105468

  15. 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.

  16. N-acetylaspartate, choline, myoinositol, glutamine and glutamate (glx) concentration changes in proton MR spectroscopy (1H MRS) in patients with mild cognitive impairment (MCI).

    PubMed

    Walecki, Jerzy; Barcikowska, Maria; Ćwikła, Jarosław B; Gabryelewicz, Tomasz

    2011-12-01

    Purpose of study was evaluation of regional metabolic disorders using 1H MRS in patients with MCI, as a predictor of clinical conversion to dementia based on clinical follow-up. The study group consisted of 31 subjects with diagnosis of MCI based on criteria the Mayo Clinic Group. ¹H MRS was performed with a single-voxel method using PRESS sequence. The volume of interest (VOI) was located in the hippocampal formation and posterior part of the cingulated gyrus. Patients had annual clinical control at least twice. At the beginning, 9 had amnestic MCI and the others had multidomain MCI. During follow-up (median 3 yrs) 8 subjects had stable disease (SD), 13 had disease progression (DP) and 10 develop Alzheimer disease (AD). Baseline metabolic ratios (1H MRS) between 3 groups indicated significant difference (P < 0.05) in left frontal lobe in mI/H20 ratio, between patients with SD (0.27) and DP. In comparing the groups with DP and AD, a significant difference in NAA/Cr (1.77 vs. 1.43) was found. A significant difference within left temporal external lobes was found between SD and DP in NAA/H2O ratio (0.55 vs. 0.51). An additional significant difference within medial temporal lobe was found between DP and AD in Glx/H2O ratio (0.44 vs. 0.34) on the right side. 1H MRS seems to be sensitive method allows prediction of which patients are liable to progress from MCI to AD. Combined with other biomarkers of disease staging, it is an important approach in the preclinical AD diagnosis, as well as the assessment of dementia progression.

  17. 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.

  18. [Total brain T2-hyperintense lesion-volume and the axonal damage in the normal-appearing white matter of brainstem in early lapsing-remitting multiple sclerosis].

    PubMed

    Pascual-Lozano, A M; Martínez-Bisbal, M C; Boscá-Blasco, I; Valero-Merino, C; Coret-Ferrer, F; Martí-Bonmatí, L; Martínez-Granados, B; Celda, B; Casanova-Estruch, B

    To evaluate the relationship between the total brain T2-hyperintense lesion volume (TBT2LV) and the axonal damage in the normal-appearing white matter of brainstem measured by 1H-MRS in a group of early relapsing-remitting multiple sclerosis patients. 40 relapsing-remitting multiple sclerosis patients and ten sex- and age-matched healthy subjects were prospectively studied for two years. T2-weighted MR and 1H-MRS imaging were acquired at time of recruitment and at year two. The TBT2LV was calculated with a semiautomatic program; N-acetylaspartate (NAA), creatine (Cr) and choline (Cho) resonances areas were integrated with jMRUI program and the ratios were calculated for four volume elements that represented the brainstem. At basal study we obtained an axonal loss (as a decrement of NAA/ Cho ratio) in the group of patients compared with controls (p = 0.017); this axonal loss increased at the second year of the follow-up for patients (NAA/Cho decrease, p = 0.004, and NAA/Cr decrease, p = 0.002) meanwhile control subjects had no significant metabolic changes. Higher lesion load was correlated with a poor clinical outcome, being the correlation between the basal TBT2LV and the Expanded Disability Status Scale at second year (r = 0.299; p = 0.05). Besides, axonal loss was not homogeneous for all multiple sclerosis patients, being stronger in the subgroup of patients with high basal TBT2LV (p = 0.043; ANOVA). Our data suggest that axonal damage is early in multiple sclerosis and higher in patients high basal TBT2LV, suggesting a possible relationship between these two phenomena.

  19. 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.

  20. 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

  1. 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.

  2. NAA and NAAG variation in neuronal activation during visual stimulation.

    PubMed

    Castellano, G; Dias, C S B; Foerster, B; Li, L M; Covolan, R J M

    2012-11-01

    N-acetyl-aspartyl-glutamate (NAAG) and its hydrolysis product N-acetyl-L-aspartate (NAA) are among the most important brain metabolites. NAA is a marker of neuron integrity and viability, while NAAG modulates glutamate release and may have a role in neuroprotection and synaptic plasticity. Investigating on a quantitative basis the role of these metabolites in brain metabolism in vivo by magnetic resonance spectroscopy (MRS) is a major challenge since the main signals of NAA and NAAG largely overlap. This is a preliminary study in which we evaluated NAA and NAAG changes during a visual stimulation experiment using functional MRS. The paradigm used consisted of a rest period (5 min and 20 s), followed by a stimulation period (10 min and 40 s) and another rest period (10 min and 40 s). MRS from 17 healthy subjects were acquired at 3T with TR/TE = 2000/288 ms. Spectra were averaged over subjects and quantified with LCModel. The main outcomes were that NAA concentration decreased by about 20% with the stimulus, while the concentration of NAAG concomitantly increased by about 200%. Such variations fall into models for the energy metabolism underlying neuronal activation that point to NAAG as being responsible for the hyperemic vascular response that causes the BOLD signal. They also agree with the fact that NAAG and NAA are present in the brain at a ratio of about 1:10, and with the fact that the only known metabolic pathway for NAAG synthesis is from NAA and glutamate.

  3. 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.

  4. 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.

  5. 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.

  6. 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

  7. 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.

  8. 3-Dimensional Magnetic Resonance Spectroscopic Imaging at 3 Tesla for Early Response Assessment of Glioblastoma Patients During External Beam Radiation Therapy

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

    Muruganandham, Manickam; Clerkin, Patrick P.; Smith, Brian J.

    Purpose: To evaluate the utility of 3-dimensional magnetic resonance (3D-MR) proton spectroscopic imaging for treatment planning and its implications for early response assessment in glioblastoma multiforme. Methods and Materials: Eighteen patients with newly diagnosed, histologically confirmed glioblastoma had 3D-MR proton spectroscopic imaging (MRSI) along with T2 and T1 gadolinium-enhanced MR images at simulation and at boost treatment planning after 17 to 20 fractions of radiation therapy. All patients received standard radiation therapy (RT) with concurrent temozolomide followed by adjuvant temozolomide. Imaging for response assessment consisted of MR scans every 2 months. Progression-free survival was defined by the criteria of MacDonald et al.more » MRSI images obtained at initial simulation were analyzed for choline/N-acetylaspartate ratios (Cho/NAA) on a voxel-by-voxel basis with abnormal activity defined as Cho/NAA ≥2. These images were compared on anatomically matched MRSI data collected after 3 weeks of RT. Changes in Cho/NAA between pretherapy and third-week RT scans were tested using Wilcoxon matched-pairs signed rank tests and correlated with progression-free survival, radiation dose and location of recurrence using Cox proportional hazards regression. Results: After a median follow-up time of 8.6 months, 50% of patients had experienced progression based on imaging. Patients with a decreased or stable mean or median Cho/NAA values had less risk of progression (P<.01). Patients with an increase in mean or median Cho/NAA values at the third-week RT scan had a significantly greater chance of early progression (P<.01). An increased Cho/NAA at the third-week MRSI scan carried a hazard ratio of 2.72 (95% confidence interval, 1.10-6.71; P=.03). Most patients received the prescription dose of RT to the Cho/NAA ≥2 volume, where recurrence most often occurred. Conclusion: Change in mean and median Cho/NAA detected at 3 weeks was a significant

  9. Distinction Between Recurrent Glioma and Radiation Injury Using Magnetic Resonance Spectroscopy in Combination With Diffusion-Weighted Imaging

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

    Zeng, Q.-S.; Li, C.-F.; Liu Hong

    2007-05-01

    Purpose: The aim of this study was to explore the diagnostic effectiveness of magnetic resonance (MR) spectroscopy with diffusion-weighted imaging on the evaluation of the recurrent contrast-enhancing areas at the site of treated gliomas. Methods and Materials: In 55 patients who had new contrast-enhancing lesions in the vicinity of the previously resected and irradiated high-grade gliomas, two-dimensional MR spectroscopy and diffusion-weighted imaging were performed. Spectral data for N-acetylaspartate (NAA), choline (Cho), creatine (Cr), lipid (Lip), and lactate (Lac) were analyzed in conjunction with the apparent diffusion coefficient (ADC) in all patients. Diagnosis of these lesions was assigned by means ofmore » follow-up or histopathology. Results: The Cho/NAA and Cho/Cr ratios were significantly higher in recurrent tumor than in regions of radiation injury (p < 0.01). The ADC value and ADC ratios (ADC of contrast-enhancing lesion to matching structure in the contralateral hemisphere) were significantly higher in radiation injury regions than in recurrent tumor (p < 0.01). With MR spectroscopic data, two variables (Cho/NAA and Cho/Cr ratios) were shown to differentiate recurrent glioma from radiation injury, and 85.5% of total subjects were correctly classified into groups. However, with discriminant analysis of MR spectroscopy imaging plus diffusion-weighted imaging, three variables (Cho/NAA, Cho/Cr, and ADC ratio) were identified and 96.4% of total subjects were correctly classified. There was a significant difference between the diagnostic accuracy of the two discriminant analyses (Chi-square = 3.96, p = 0.046). Conclusion: Using discriminant analysis, this study found that MR spectroscopy in combination with ADC ratio, rather than ADC value, can improve the ability to differentiate recurrent glioma and radiation injury.« less

  10. Serial proton MR spectroscopy of gray and white matter in relapsing-remitting MS

    PubMed Central

    Kirov, Ivan I.; Tal, Assaf; Babb, James S.; Herbert, Joseph

    2013-01-01

    Objective: To characterize and follow the diffuse gray and white matter (GM/WM) metabolic abnormalities in early relapsing-remitting multiple sclerosis using proton magnetic resonance spectroscopic imaging (1H-MRSI). Methods: Eighteen recently diagnosed, mildly disabled patients (mean baseline time from diagnosis 32 months, mean Expanded Disability Status Scale [EDSS] score 1.3), all on immunomodulatory medication, were scanned semiannually for 3 years with T1-weighted and T2-weighted MRI and 3D 1H-MRSI at 3 T. Ten sex- and age-matched controls were followed annually. Global absolute concentrations of N-acetylaspartate (NAA), choline (Cho), creatine (Cr), and myo-inositol (mI) were obtained for all GM and WM in the 360 cm3 1H-MRSI volume of interest. Results: Patients' average WM Cr, Cho, and mI concentrations (over all time points), 5.3 ± 0.4, 1.6 ± 0.1, and 5.1 ± 0.7 mM, were 8%, 12%, and 11% higher than controls' (p ≤ 0.01), while their WM NAA, 7.4 ± 0.7 mM, was 6% lower (p = 0.07). There were increases with time of patients' WM Cr: 0.1 mM/year, Cho: 0.02 mM/year, and NAA: 0.1 mM/year (all p < 0.05). None of the patients' metabolic concentrations correlated with their EDSS score, relapse rate, GM/WM/CSF fractions, or lesion volume. Conclusions: Diffuse WM glial abnormalities were larger in magnitude than the axonal abnormalities and increased over time independently of conventional clinical or imaging metrics and despite immunomodulatory treatment. In contrast, the axonal abnormalities showed partial recovery, suggesting that patients' lower WM NAA levels represented a dysfunction, which may abate with treatment. Absence of detectable diffuse changes in GM suggests that injury there is minimal, focal, or heterogeneous between cortex and deep GM nuclei. PMID:23175732

  11. 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.

  12. Altered white matter metabolism in delayed neurologic sequelae after carbon monoxide poisoning: A proton magnetic resonance spectroscopic study.

    PubMed

    Kuroda, Hiroshi; Fujihara, Kazuo; Mugikura, Shunji; Takahashi, Shoki; Kushimoto, Shigeki; Aoki, Masashi

    2016-01-15

    Proton magnetic resonance spectroscopy ((1)H-MRS) was recently used to examine altered metabolism in the white matter (WM) of patients experiencing carbon monoxide (CO) poisoning; however, only a small number of patients with delayed neurologic sequelae (DNS) were analyzed. We aimed to detect altered metabolism in the WM of patients with DNS using (1)H-MRS; to explore its clinical relevance in the management of patients experiencing CO poisoning. Patients experiencing acute CO poisoning underwent (1)H-MRS and cerebrospinal fluid (CSF) examination within 1week and at 1month after acute poisoning. Metabolites including choline-containing compounds (Cho), creatine (Cr), N-acetylaspartate (NAA), and lactate were measured from the periventricular WM. Myelin basic protein (MBP) concentrations were measured in CSF. Fifty-two patients experiencing acute CO poisoning (15 with DNS, 37 without DNS; median age, 49years; 65% males) underwent (1)H-MRS. Within 1week, NAA/Cr ratios, reflecting neuroaxonal viability, were lower in patients with DNS than in those without DNS (P<0.05). At 1month, when 9 of 15 patients (60%) developed DNS, Cho/Cr ratios were higher, and NAA/Cr and NAA/Cho ratios lower in patients with DNS (P=0.0001, <0.0001, and <0.0001, respectively), indicating increased membrane metabolism and decreased neuroaxonal viability. (1)H-MRS parameter abnormalities correlated with the elevation of MBP in CSF. The presence of a lactate peak was a predictor for a poor long-term outcome. (1)H-MRS within 1week may be useful for predicting DNS development; (1)H-MRS at 1month may be useful for discriminating patients with DNS and predicting long-term outcomes. Copyright © 2015 Elsevier B.V. All rights reserved.

  13. Central N-acetyl aspartylglutamate deficit: a possible pathogenesis of schizophrenia.

    PubMed

    Tsai, Shih-Jen

    2005-09-01

    The "glutamate hypothesis" of schizophrenia has emerged from the finding that phencyclidine (PCP) induces psychotic-like behaviors in rodents, possibly by blocking the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor, thereby causing increased glutamate release. N-acetyl aspartylglutamate (NAAG), an endogenous peptide abundant in mammalian nervous systems, is localized in certain brain cells, including cortical and hippocampal pyramidal neurons. NAAG is synthesized from N-acetylaspartate (NAA) and glutamate, and NAA availability may limit the rate of NAAG synthesis. Although NAAG is known to have some neurotransmitter-like functions, NAA does not. NAAG is a highly selective agonist of the type 3 metabotropic glutamate receptor (mGluR3, a presynaptic autoreceptor) and can inhibit glutamate release. In addition, at low levels, NAAG is an NMDA receptor antagonist, and blocking of NMDA receptors may increase glutamate release. Taken together, low central NAAG levels may antagonize the effect of glutamate at NMDA receptors and decrease its agonistic effect on presynaptic mGluR3; both activities could increase glutamate release, similar to the increase demonstrated in the PCP model of schizophrenia. In this report, it is suggested that the central NAAG deficit, possibly through decreased synthesis or increased degradation of NAAG, may play a role in the pathogenesis of schizophrenia. Evidence is presented and discussed from magnetic resonance, postmortem, animal model, schizophrenia treatment, and genetic studies. The central NAAG deficit model of schizophrenia could explain the disease process, from the perspectives of both neurodevelopment and neurodegeneration, and may point to potential treatments for schizophrenia.

  14. 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.

  15. 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

  16. 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.

  17. Age-modulated association between prefrontal NAA and the BDNF gene.

    PubMed

    Salehi, Basira; Preuss, Nora; van der Veen, Jan Willem; Shen, Jun; Neumeister, Alexander; Drevets, Wayne C; Hodgkinson, Colin; Goldman, David; Wendland, Jens R; Singleton, Andrew; Gibbs, Jesse R; Cookson, Mark R; Hasler, Gregor

    2013-07-01

    Brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of psychiatric and neurological disorders and in the mechanisms of antidepressant pharmacotherapy. Psychiatric and neurological conditions have also been associated with reduced brain levels of N-acetyl-aspartate (NAA), which has been used as a putative marker of neural integrity. However, few studies have explored the relationship between BDNF polymorphisms and NAA levels directly. Here, we present data from a single-voxel proton magnetic resonance spectroscopy study of 64 individuals and explore the relationship between BDNF polymorphisms and prefrontal NAA level. Our results indicate an association between a single nucleotide polymorphism (SNP) within BDNF, known as rs1519480, and reduced NAA level (p = 0.023). NAA levels were further predicted by age and Asian ancestry. There was a significant rs1519480 × age interaction on NAA level (p = 0.031). Specifically, the effect of rs1519480 on NAA level became significant at age ⩾34.17 yr. NAA level decreased with advancing age for genotype TT (p = 0.001) but not for genotype CT (p = 0.82) or CC (p = 0.34). Additional in silico analysis of 142 post-mortem brain samples revealed an association between the same SNP and reduced BDNF mRNA expression in the prefrontal cortex. The rs1519480 SNP influences BDNF mRNA expression and has an impact on prefrontal NAA level over time. This genetic mechanism may contribute to inter-individual variation in cognitive performance seen during normal ageing, as well as contributing to the risk for developing psychiatric and neurological conditions.

  18. 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

  19. 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.

  20. 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.

  1. 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

  2. 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.

  3. 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.

  4. Integrative Network-based Analysis of Magnetic Resonance Spectroscopy and Genome Wide Expression in Glioblastoma multiforme

    PubMed Central

    Heiland, Dieter Henrik; Mader, Irina; Schlosser, Pascal; Pfeifer, Dietmar; Carro, Maria Stella; Lange, Thomas; Schwarzwald, Ralf; Vasilikos, Ioannis; Urbach, Horst; Weyerbrock, Astrid

    2016-01-01

    The goal of this study was to identify correlations between metabolites from proton MR spectroscopy and genetic pathway activity in glioblastoma multiforme (GBM). Twenty patients with primary GBM were analysed by short echo-time chemical shift imaging and genome-wide expression analyses. Weighed Gene Co-Expression Analysis was used for an integrative analysis of imaging and genetic data. N-acetylaspartate, normalised to the contralateral healthy side (nNAA), was significantly correlated to oligodendrocytic and neural development. For normalised creatine (nCr), a group with low nCr was linked to the mesenchymal subtype, while high nCr could be assigned to the proneural subtype. Moreover, clustering of normalised glutamine and glutamate (nGlx) revealed two groups, one with high nGlx being attributed to the neural subtype, and one with low nGlx associated with the classical subtype. Hence, the metabolites nNAA, nCr, and nGlx correlate with a specific gene expression pattern reflecting the previously described subtypes of GBM. Moreover high nNAA was associated with better clinical prognosis, whereas patients with lower nNAA revealed a shorter progression-free survival (PFS). PMID:27350391

  5. 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

  6. 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.

  7. Long-term Brain Tissue Monitoring after Semi-brain Irradiation in Rats Using Proton Magnetic Resonance Spectroscopy: A Preliminary Study In vivo

    PubMed Central

    Chen, Hong; Cheng, Yu-Shu; Zhou, Zheng-Rong

    2017-01-01

    Background: In head and neck neoplasm survivors treated with brain irradiation, metabolic alterations would occur in the radiation-induced injury area. The mechanism of these metabolic alterations has not been fully understood, while the alternations could be sensitively detected by proton (1H) nuclear magnetic resonance spectroscopy (MRS). In this study, we investigated the metabolic characteristics of radiation-induced brain injury through a long-term follow-up after radiation treatment using MRS in vivo. Methods: A total of 12 adult Sprague-Dawley rats received a single dose of 30 Gy radiation treatment to semi-brain (field size: 1.0 cm × 2.0 cm; anterior limit: binocular posterior inner canthus connection; posterior limit: external acoustic meatus connection; internal limit: sagittal suture). Conventional magnetic resonance imaging and single-voxel 1H-MRS were performed at different time points (in month 0 before irradiation as well as in the 1st, 3rd, 5th, 7th, and 9th months after irradiation) to investigate the alternations in irradiation field. N-acetylaspartate/choline (NAA/Cho), NAA/creatinine (Cr), and Cho/Cr ratios were measured in the bilateral hippocampus and quantitatively analyzed with a repeated-measures mixed-effects model and multiple comparison test. Results: Significant changes in the ratios of NAA/Cho (F = 57.37, Pg < 0.001), NAA/Cr (F = 54.49, Pg < 0.001), and Cho/Cr (F = 9.78, Pg = 0.005) between the hippocampus region of the irradiated semi-brain and the contralateral semi-brain were observed. There were significant differences in NAA/Cho (F = 9.17, Pt < 0.001) and NAA/Cr (F = 13.04, Pt < 0.001) ratios over time. The tendency of NAA/Cr to change with time showed no significant difference between the irradiated and contralateral sides. Nevertheless, there were significant differences in the Cho/Cr ratio between these two sides. Conclusions: MRS can sensitively detect metabolic alternations. Significant changes of metabolites ratio in the

  8. Similarities of biochemical abnormalities between major depressive disorder and bipolar depression: a proton magnetic resonance spectroscopy study.

    PubMed

    Zhong, Shuming; Wang, Ying; Zhao, Guoxiang; Xiang, Qi; Ling, Xueying; Liu, Sirun; Huang, Li; Jia, Yanbin

    2014-10-01

    Depression in the context of bipolar disorder (BD) is often misdiagnosed as major depressive disorder (MDD), leading to mistreatments and poor clinical outcomes for many bipolar patients. Previous neuroimaging studies found mixed results on brain structure, and biochemical metabolism of the two disorders. To eliminate the compounding effects of medication, and aging, this study sought to investigate the brain biochemical changes of treatment-naïve, non-late-life patients with MDD and BD in white matter in prefrontal (WMP) lobe, anterior cingulate cortex (ACC) and hippocampus by using proton magnetic resonance spectroscopy ((1)H-MRS). Three groups of participants were recruited: 26 MDD patients, 20 depressed BD patients, and 13 healthy controls. The multi-voxel (1)H-MRS [repetition time (TR)=1000ms; echo-time (TE)=144ms] was used for the measurement of N-acetylaspartate(NAA), choline containg compounds (Cho), and creatine (Cr) in three brain locations: white matter in prefrontal (WMP) lobe, anterior cingulate cortex (ACC), and hippocampus. Two ratios of NAA/Cr and Cho/Cr as a measure of brain biochemical changes were compared among three experimental groups. On the comparison of brain biochemical changes, both MDD patients and BD patients showed many similarities compared to the controls. They both had a significantly lower NAA/Cr ratio in the left WMP lobe. There were no significant differences among three experimental groups for Cho/Cr ratio in the WMP lobe, and for the ratios of NAA/Cr and Cho/Cr in the bilateral ACC and hippocampus. The only difference between MDD and BD patients existed for the NAA/Cr ratio in the right WMP lobe. While MDD patients had a significantly lower NAA/Cr ratio than controls, BD patients showed no such differences. On the comparison of correlation of medical variables and brain biochemical changes, all participants demonstrated no significant correlations. Reduced NAA/Cr ratio at the left WMP lobe indicated the dysfunction of neuronal

  9. 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

  10. Decreases in Short Term Memory, IQ, and Altered Brain Metabolic Ratios in Urban Apolipoprotein ε4 Children Exposed to Air Pollution.

    PubMed

    Calderón-Garcidueñas, Lilian; Mora-Tiscareño, Antonieta; Franco-Lira, Maricela; Zhu, Hongtu; Lu, Zhaohua; Solorio, Edelmira; Torres-Jardón, Ricardo; D'Angiulli, Amedeo

    2015-01-01

    Children's urban air pollution exposures result in systemic and brain inflammation and the early hallmarks of Alzheimer's disease (AD). The apolipoprotein E (APOE) ε4 allele is the most prevalent genetic risk for AD. We assessed whether APOE in healthy children modulates cognition, olfaction, and metabolic brain indices. The Wechsler Intelligence Scale for Children (WISC-R) and the University of Pennsylvania Smell Identification Test were administered to 50 Mexico City Metropolitan Area children (13.4 ± 4.8 years, 28 APOE ε3 and 22 APOE ε4). N-acetylaspartate (NAA)/creatine (Cr), choline (Cho)/Cr, myo-inositol (mI)/Cr, and NAA/mI were calculated using proton magnetic resonance spectroscopy in the white matter of the frontal and parietal lobes, hippocampus, and pons. APOE ε4 versus ε3 children had a reduced NAA/Cr ratio in the right frontal white matter and decrements on attention, short-term memory, and below-average scores in Verbal and Full Scale IQ (>10 points). APOE modulated the group effects between WISC-R and left frontal and parietal white matter, and hippocampus metabolites. Soap was the predominantly failed odor in urban children and, in APOE ε4 versus ε3 carriers, strongly correlated with left hippocampus mI/Cr ratio. APOE modulates responses to air pollution in the developing brain. APOE ε4 carriers could have a higher risk of developing early AD if they reside in a polluted environment. APOE, cognition, and olfaction testing and targeted magnetic resonance spectroscopy may contribute to the assessment of urban children and their results could provide new paths toward the unprecedented opportunity for early neuroprotection and AD prevention.

  11. 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.

  12. Structure and function of human Naa60 (NatF), a Golgi-localized bi-functional acetyltransferase

    DOE PAGES

    Chen, Ji-Yun; Liu, Liang; Cao, Chun-Ling; ...

    2016-08-23

    N-terminal acetylation (Nt-acetylation), carried out by N-terminal acetyltransferases (NATs), is a conserved and primary modification of nascent peptide chains. Naa60 (also named NatF) is a recently identified NAT found only in multicellular eukaryotes. This protein was shown to locate on the Golgi apparatus and mainly catalyze the Nt-acetylation of transmembrane proteins, and it also harbors lysine Nε -acetyltransferase (KAT) activity to catalyze the acetylation of lysine ε-amine. Here, we report the crystal structures of human Naa60 (hNaa60) in complex with Acetyl-Coenzyme A (Ac-CoA) or Coenzyme A (CoA). The hNaa60 protein contains an amphipathic helix following its GNAT domain that maymore » contribute to Golgi localization of hNaa60, and the β7-β8 hairpin adopted different conformations in the hNaa60(1-242) and hNaa60(1-199) crystal structures. Remarkably, we found that the side-chain of Phe 34 can influence the position of the coenzyme, indicating a new regulatory mechanism involving enzyme, co-factor and substrates interactions. Moreover, structural comparison and biochemical studies indicated that Tyr 97 and His 138 are key residues for catalytic reaction and that a non-conserved β3-β4 long loop participates in the regulation of hNaa60 activity.« less

  13. 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.

  14. 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

  15. 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

  16. Proton magnetic resonance spectroscopy as a probe into the pathophysiology of autism spectrum disorders (ASD): a review.

    PubMed

    Baruth, Joshua M; Wall, Christopher A; Patterson, Marc C; Port, John D

    2013-04-01

    Proton magnetic resonance spectroscopy ((1) H-MRS) is a safe, noninvasive way of quantifying in vivo biochemical and metabolite concentration levels in individuals with Autism Spectrum Disorders (ASD). Findings to date suggest ASD is associated with widespread reduction in N-acetylaspartate (NAA), creatine plus phosphocreatine (Cr), choline-containing compounds (Cho), myo-inositol (mI), and glutamate plus glutamine plus gamma-Aminobutyric Acid (Glx); however, variable findings, and even substantial increases, are not uncommon depending on the study and/or region-of-interest. Widespread reduction of NAA, Cr, Cho, mI, and Glx in ASD likely reflects impaired neuronal function and/or metabolism related to abnormal neurodevelopmental processes. Future studies should attempt to relate (1) H-MRS findings to histological findings and control for variability in subject age and functioning level; this would assist in evaluating the relationship between (1) H-MRS metabolic levels and neuronal and glial cell densities, as well as neurodevelopmental process associated with ASD. Furthermore, more longitudinal (1) H-MRS studies are needed in both control and ASD subjects to attempt to standardize metabolite levels across different developmental periods in well-defined endophenotypes. This will provide for a standard rubric for which metabolic aberrations (as well as treatment responses) can be measured. With higher magnetic field strengths and spectral-editing techniques capable of quantifying less-concentrated metabolites, (1) H-MRS will continue to be an important tool in ASD research. © 2013 International Society for Autism Research, Wiley Periodicals, Inc.

  17. A preliminary examination of cortical neurotransmitter levels associated with heavy drinking in posttraumatic stress disorder.

    PubMed

    Pennington, David Louis; Abé, Christoph; Batki, Steven Laszlo; Meyerhoff, Dieter Johannes

    2014-12-30

    Posttraumatic stress disorder (PTSD) patients have low cortical concentrations of γ-aminobutyric acid (GABA) and elevated glutamate (Glu) as measured by proton magnetic resonance spectroscopy ((1)H MRS). Alcohol use disorder (AUD) is highly comorbid with PTSD, but the neurobiological underpinnings are largely unknown. We wanted to determine if PTSD patients with AUD have normalized cortical GABA and Glu levels in addition to metabolite alterations common to AUD. We compared brain metabolite concentrations in 10 PTSD patients with comorbid AUD (PAUD) with concentrtations in 28 PTSD patients without AUD and in 20 trauma-exposed controls (CON) without PTSD symptoms. We measured concentrations of GABA, Glu, N-acetylaspartate (NAA), creatine- (Cr) and choline-containing metabolites (Cho), and myo-Inositol (mI) in three cortical brain regions using (1)H MRS and correlated them with measures of neurocognition, insomnia, PTSD symptoms, and drinking severity. In contrast to PTSD, PAUD exhibited normal GABA and Glu concentrations in the parieto-occipital and temporal cortices, respectively, but lower Glu and trends toward higher GABA levels in the anterior cingulate cortex (ACC). Temporal NAA and Cho as well as mI in the ACC were lower in PAUD than in both PTSD and CON. Within PAUD, more cortical GABA and Glu correlated with better neurocognition. Heavy drinking in PTSD is associated with partially neutralized neurotransmitter imbalance, but also with neuronal injury commonly observed in AUD. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  18. 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

  19. Proton Magnetic Resonance Spectroscopy in Social Anxiety Disorder.

    PubMed

    Tükel, Raşit; Aydın, Kubilay; Yüksel, Çağrı; Ertekin, Erhan; Koyuncu, Ahmet

    2016-01-01

    In the present study, 24 nonmedicated patients with social anxiety disorder (SAD) were compared with 24 healthy control subjects to assess metabolite levels in the anterior cingulate, insula, caudate, and putamen using proton magnetic resonance spectroscopy. The ratio of N-acetylaspartate (NAA)/creatine (Cr) was significantly higher in patients with SAD than in healthy control subjects in the anterior cingulate and insula. NAA/Cr ratios in the insula correlated positively with the Liebowitz Social Anxiety Scale total scores in patients with SAD. Our results support the significance and biochemical involvement of the anterior cingulate and insula in the pathophysiology of SAD.

  20. 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.

  1. Metabolic Acetate Therapy for the Treatment of Traumatic Brain Injury

    PubMed Central

    Arun, Peethambaran; Ariyannur, Prasanth S.; Moffett, John R.; Xing, Guoqiang; Hamilton, Kristen; Grunberg, Neil E.; Ives, John A.

    2010-01-01

    Abstract Patients suffering from traumatic brain injury (TBI) have decreased markers of energy metabolism, including N-acetylaspartate (NAA) and ATP. In the nervous system, NAA-derived acetate provides acetyl-CoA required for myelin lipid synthesis. Acetate can also be oxidized in mitochondria for the derivation of metabolic energy. In the current study, using the controlled cortical impact model of TBI in rats, we investigated the effects of the hydrophobic acetate precursor, glyceryltriacetate (GTA), as a method of delivering metabolizable acetate to the injured brain. We found that GTA administration significantly increased the levels of both NAA and ATP in the injured hemisphere 4 and 6 days after injury, and also resulted in significantly improved motor performance in rats 3 days after injury. PMID:19803785

  2. Metabolic acetate therapy for the treatment of traumatic brain injury.

    PubMed

    Arun, Peethambaran; Ariyannur, Prasanth S; Moffett, John R; Xing, Guoqiang; Hamilton, Kristen; Grunberg, Neil E; Ives, John A; Namboodiri, Aryan M A

    2010-01-01

    Patients suffering from traumatic brain injury (TBI) have decreased markers of energy metabolism, including N-acetylaspartate (NAA) and ATP. In the nervous system, NAA-derived acetate provides acetyl-CoA required for myelin lipid synthesis. Acetate can also be oxidized in mitochondria for the derivation of metabolic energy. In the current study, using the controlled cortical impact model of TBI in rats, we investigated the effects of the hydrophobic acetate precursor, glyceryltriacetate (GTA), as a method of delivering metabolizable acetate to the injured brain. We found that GTA administration significantly increased the levels of both NAA and ATP in the injured hemisphere 4 and 6 days after injury, and also resulted in significantly improved motor performance in rats 3 days after injury.

  3. 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%.

  4. 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.

  5. 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.

  6. 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.

  7. Local and downstream effects of excitotoxic lesions in the rat medial prefrontal cortex on In vivo 1H-MRS signals.

    PubMed

    Roffman, J L; Lipska, B K; Bertolino, A; Van Gelderen, P; Olson, A W; Khaing, Z Z; Weinberger, D R

    2000-04-01

    The rat medial prefrontal cortex (mPFC) regulates subcortical dopamine transmission via projections to the striatum and ventral tegmental area. We used in vivo proton magnetic resonance spectroscopy (1H-MRS) at 4.7 T to determine whether excitotoxic lesions of the mPFC result in alterations of N-acetylaspartate (NAA), a marker of neuronal integrity, both locally and downstream in the striatum. Lesioned rats exhibited persistent reductions of NAA and other metabolites within the prefrontal cortex; selective reductions of NAA were seen in the striatum, but not in the parietal cortex. Consistent with earlier reports, lesioned rats exhibited a transient enhancement in amphetamine-induced hyperlocomotion. Prefrontal NAA losses correlated with lesion extent. In the striatum, while there was no change in tissue volume, expression of striatal glutamic acid decarboxylase-67 mRNA was significantly reduced. In vivo NAA levels thus appear sensitive to both local and downstream alterations in neuronal integrity, and may signal meaningful effects at cellular and behavioral levels.

  8. 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

  9. 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.

  10. 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

  11. 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.

  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. 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.

  14. 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.

  15. NaA zeolite derived from blast furnace slag: its application for ammonium removal.

    PubMed

    Guo, Hongwei; Tang, Lizhen; Yan, Bingji; Wan, Kang; Li, Peng

    2017-09-01

    In this paper, high value added NaA zeolite material was prepared from blast furnace (BF) slag by hydrothermal method and its adsorption behavior on the removal of ammonium ion was investigated. It was found out that the synthetic NaA cubic zeolite with smaller crystal size obtained at nSiO 2 /nAl 2 O 3 = 2 and nH 2 O/nNaOH = 20 showed better adsorption performance. The kinetics of the adsorption of ammonium ion by synthesized NaA zeolite was fitted by the pseudo-second-order kinetic model. The intra-particle diffusion modeling reveals that two mixed rate-controlling mechanisms were involved in the adsorption process. The relatively high value of activation energy of 92.3 kJ·mol -1 indicates a high impact of temperature on the adsorption rate, and the nature of ammonium adsorption is chemical reaction rather than physisorption. Based on the thermodynamics calculations, the adsorption of ammonium was found to be an endothermic, spontaneous process. The adsorption isothermal analysis showed that the Langmuir model could be well fitted and a maximum adsorption capacity of 83.3 mg·g -1 of NH 4 + was obtained. Thus, it was demonstrated that by forming low cost NaA zeolite and using it for environmental remediation, the synchronous minimization of BF slag and ammonia nitrogen contamination could be achieved.

  16. 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

  17. 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.

  18. 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.

  19. 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

  20. 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

  1. Neurometabolite Alterations Associated With Cognitive Performance in Perinatally HIV-Infected Children.

    PubMed

    Van Dalen, Yvonne W; Blokhuis, Charlotte; Cohen, Sophie; Ter Stege, Jacqueline A; Teunissen, Charlotte E; Kuhle, Jens; Kootstra, Neeltje A; Scherpbier, Henriette J; Kuijpers, Taco W; Reiss, Peter; Majoie, Charles B L M; Caan, Matthan W A; Pajkrt, Dasja

    2016-03-01

    Despite treatment with combination antiretroviral therapy (cART), cognitive impairment is still observed in perinatally HIV-infected children. We aimed to evaluate potential underlying cerebral injury by comparing neurometabolite levels between perinatally HIV-infected children and healthy controls. This cross-sectional study evaluated neurometabolites, as measured by Magnetic Resonance Spectroscopy (MRS), in perinatally HIV-infected children stable on cART (n = 26) and healthy controls (n = 36).Participants were included from a cohort of perinatally HIV-infected children and healthy controls, matched group-wise for age, gender, ethnicity, and socio-economic status. N-acetylaspartate (NAA), glutamate (Glu), myo-inositol (mI), and choline (Cho) levels were studied as ratios over creatine (Cre). Group differences and associations with HIV-related parameters, cognitive functioning, and neuronal damage markers (neurofilament and total Tau proteins) were determined using age-adjusted linear regression analyses.HIV-infected children had increased Cho:Cre in white matter (HIV-infected = 0.29 ± 0.03; controls = 0.27 ± 0.03; P value = 0.045). Lower nadir CD4+ T-cell Z-scores were associated with reduced neuronal integrity markers NAA:Cre and Glu:Cre. A Centers for Disease Control and Prevention (CDC) stage C diagnosis was associated with higher glial markers Cho:Cre and mI:Cre. Poorer cognitive performance was mainly associated with higher Cho:Cre in HIV-infected children, and with lower NAA:Cre and Glu:Cre in healthy controls. There were no associations between neurometabolites and neuronal damage markers in blood or CSF.Compared to controls, perinatally HIV-infected children had increased Cho:Cre in white matter, suggestive of ongoing glial proliferation. Levels of several neurometabolites were associated with cognitive performance, suggesting that MRS may be a useful method to assess cerebral changes potentially linked to cognitive outcomes.

  2. Structure-specific glial response in a macaque model of neuroAIDS: multivoxel proton magnetic resonance spectroscopic imaging at 3 Tesla.

    PubMed

    Wu, William E; Tal, Assaf; Zhang, Ke; Babb, James S; Ratai, Eva-Maria; González, R Gilberto; Gonen, Oded

    2013-10-23

    As ~40% of persons with HIV also suffer neurocognitive decline, we sought to assess metabolic dysfunction in the brains of simian immunodeficiency virus (SIV)-infected rhesus macaques, an advanced animal model, in structures involved in cognitive function. We test the hypothesis that SIV-infection produces proton-magnetic resonance spectroscopic imaging (H-MRSI)-observed decline in the neuronal marker, N-acetylaspartate (NAA), and elevations in the glial marker, myo-inositol (mI), and associated creatine (Cr) and choline (Cho) in these structures. Pre- and 4-6 weeks post-SIV infection (with CD8 T-lymphocyte depletion) was monitored with T2-weighted quantitative MRI and 16×16×4 multivoxel H-MRSI (TE/TR = 33/1400 ms) in the brains of five rhesus macaques. Exploiting the high-resolution H-MRSI grid, we obtained absolute, cerebrospinal fluid partial volume-corrected NAA, Cr, Cho and mI concentrations from centrum semiovale, caudate nucleus, putamen, thalamus and hippocampus regions. Pre- to post-infection mean Cr increased in the thalamus: 7.2±0.4 to 8.0±0.8 mmol/l (+11%, P<0.05); mI increased in the centrum semiovale: 5.1±0.8 to 6.6±0.8 mmol/l, caudate: 5.7±0.7 to 7.3±0.5 mmol/l, thalamus: 6.8±0.8 to 8.5±0.8 mmol/l and hippocampus: 7.7±1.2 to 9.9±0.4 mmol/l (+29%, +27%, +24% and +29%, all P<0.05). NAA and Cho changes were not significant. SIV-infection appears to cause brain injury indirectly, through glial activation, while the deep gray matter structures' neuronal cell bodies are relatively spared. Treatment regimens to reduce gliosis may, therefore, prevent neuronal damage and its associated neurocognitive impairment.

  3. Comparative test-retest reliability of metabolite values assessed with magnetic resonance spectroscopy of the brain. The LCModel versus the manufacturer software.

    PubMed

    Fayed, Nicolas; Modrego, Pedro J; Medrano, Jaime

    2009-06-01

    Reproducibility is an essential strength of any diagnostic technique for cross-sectional and longitudinal works. To determine in vivo short-term comparatively, the test-retest reliability of magnetic resonance spectroscopy (MRS) of the brain was compared using the manufacturer's software package and the widely used linear combination of model (LCModel) technique. Single-voxel H-MRS was performed in a series of patients with different pathologies on a 1.5 T clinical scanner. Four areas of the brain were explored with the point resolved spectroscopy technique acquisition mode; the echo time was 35 milliseconds and the repetition time was 2000 milliseconds. We enrolled 15 patients for every area, and the intra-individual variations of metabolites were studied in two consecutive scans without removing the patient from the scanner. Curve fitting and analysis of metabolites were made with the software of GE and the LCModel. Spectra non-fulfilling the minimum criteria of quality in relation to linewidths and signal/noise ratio were rejected. The intraclass correlation coefficients for the N-acetylaspartate/creatine (NAA/Cr) ratios were 0.93, 0.89, 0.9 and 0.8 for the posterior cingulate gyrus, occipital, prefrontal and temporal regions, respectively, with the GE software. For the LCModel, the coefficients were 0.9, 0.89, 0.87 and 0.84, respectively. For the absolute value of NAA, the GE software was also slightly more reproducible than LCModel. However, for the choline/Cr and myo-inositol/Cr ratios, the LCModel was more reliable than the GE software. The variability we have seen hovers around the percentages observed in previous reports (around 10% for the NAA/Cr ratios). We did not find that the LCModel software is superior to the software of the manufacturer. Reproducibility of metabolite values relies more on the observance of the quality parameters than on the software used.

  4. 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.

  5. 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.

  6. 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.

  7. 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

  8. Diffusion properties of NAA in human corpus callosum as studied with diffusion tensor spectroscopy.

    PubMed

    Upadhyay, Jaymin; Hallock, Kevin; Erb, Kelley; Kim, Dae-Shik; Ronen, Itamar

    2007-11-01

    In diffusion tensor imaging (DTI) the anisotropic movement of water is exploited to characterize microstructure. One confounding issue of DTI is the presence of intra- and extracellular components contributing to the measured diffusivity. This causes an ambiguity in determining the underlying cause of diffusion properties, particularly the fractional anisotropy (FA). In this study an intracellular constituent, N-acetyl aspartate (NAA), was used to probe intracellular diffusion, while water molecules were used to probe the combined intra- and extracellular diffusion. NAA and water diffusion measurements were made in anterior and medial corpus callosum (CC) regions, which are referred to as R1 and R2, respectively. FA(NAA) was found to be greater than FA(Water) in both CC regions, thus indicating a higher degree of anisotropy within the intracellular space in comparison to the combined intra- and extracellular spaces. A decreasing trend in the FA of NAA and water was observed between R1 and R2, while the radial diffusivity (RD) for both molecules increased. The increase in RD(NAA) is particularly significant, thus explaining the more significant decrease in FA(NAA) between the two regions. It is suggested that diffusion tensor spectroscopy of NAA can potentially be used to further characterize microscopic anatomic organization in white matter. Copyright 2007 Wiley-Liss, Inc.

  9. Amino acid metabolic processes in the temporal lobes assessed by proton magnetic resonance spectroscopy (1H MRS) in children with Down syndrome.

    PubMed

    Śmigielska-Kuzia, Joanna; Boćkowski, Leszek; Sobaniec, Wojciech; Kułak, Wojciech; Sendrowski, Krzysztof

    2010-01-01

    Down syndrome (DS), or trisomy 21, is one of the most common autosomal mutations. The overexpression of the β-amyloid precursor protein gene, located on chromosome 21, causes an increased production of the specific amyloid. The current study is a continuation of our earlier investigations relating to the profile of metabolic changes in the frontal lobes of DS patients as assessed by proton magnetic resonance spectroscopy ((1)H MRS). The aims of the study were the morphological assessment of the brain using magnetic resonance imaging (MRI) and the evaluation of metabolic disorders of the temporal lobes using (1)H MRS in DS children. The study group included 20 children with DS aged 3-15 years and treated in the Department of Pediatric Neurology and Rehabilitation, Medical University of Białystok. The control group included healthy children (n = 20). MRI scans of the heads of DS children were performed using a 1.5 T MR scanner under standard conditions. (1)H MRS investigations were also carried out to assess metabolic changes in the temporal lobes. Metabolites, such as N-acetylaspartate (NAA), glutamate-glutamine complex (Glx), choline (Cho), myoinositol (mI) and γ-aminobutyric acid (GABA), were determined in both temporal lobes with reference to the internal marker creatine (Cr). Results were compared with the control group.We found a statistically significant decrease in NAA/Cr, Cho/Cr, mI/Cr and GABA/Cr ratios. The Glx/Cr ratio in both temporal lobes of DS patients did not differ from the control group. Our results indicate metabolic neurotransmitter disorders in the central nervous system in children with DS.

  10. Whole Brain Magnetic Resonance Spectroscopic Determinants of Functional Outcomes in Pediatric Moderate/Severe Traumatic Brain Injury.

    PubMed

    Babikian, Talin; Alger, Jeffry R; Ellis-Blied, Monica U; Giza, Christopher C; Dennis, Emily; Olsen, Alexander; Mink, Richard; Babbitt, Christopher; Johnson, Jeff; Thompson, Paul M; Asarnow, Robert F

    2018-05-18

    Diffuse axonal injury contributes to the long-term functional morbidity observed after pediatric moderate/severe traumatic brain injury (msTBI). Whole-brain proton magnetic resonance echo-planar spectroscopic imaging was used to measure the neurometabolite levels in the brain to delineate the course of disruption/repair during the first year post-msTBI. The association between metabolite biomarkers and functional measures (cognitive functioning and corpus callosum [CC] function assessed by interhemispheric transfer time [IHTT] using an event related potential paradigm) was also explored. Pediatric patients with msTBI underwent assessments at two times (post-acutely at a mean of three months post-injury, n = 31, and chronically at a mean of 16 months post-injury, n = 24). Healthy controls also underwent two evaluations, approximately 12 months apart. Post-acutely, in patients with msTBI, there were elevations in choline (Cho; marker for inflammation and/or altered membrane metabolism) in all four brain lobes and the CC and decreases in N-acetylaspartate (NAA; marker for neuronal and axonal integrity) in the CC compared with controls, all of which normalized by the chronic time point. Subgroups of TBI showed variable patterns chronically. Patients with slow IHTT had lower lobar Cho chronically than those with normal IHTT; they also did not show normalization in CC NAA whereas those with normal IHTT showed significantly higher levels of CC NAA relative to controls. In the normal IHTT group only, chronic CC Cho and NAA together explained 70% of the variance in long-term cognitive functioning. MR based whole brain metabolic evaluations show different patterns of neurochemistry after msTBI in two subgroups with different outcomes. There is a dynamic relationship between prolonged inflammatory responses to brain damage, reparative processes/remyelination, and subsequent neurobehavioral outcomes. Multimodal studies allow us to test hypotheses about degenerative and

  11. SU-F-J-93: Automated Segmentation of High-Resolution 3D WholeBrain Spectroscopic MRI for Glioblastoma Treatment Planning

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

    Schreibmann, E; Shu, H; Cordova, J

    Purpose: We report on an automated segmentation algorithm for defining radiation therapy target volumes using spectroscopic MR images (sMRI) acquired at nominal voxel resolution of 100 microliters. Methods: Wholebrain sMRI combining 3D echo-planar spectroscopic imaging, generalized auto-calibrating partially-parallel acquisitions, and elliptical k-space encoding were conducted on 3T MRI scanner with 32-channel head coil array creating images. Metabolite maps generated include choline (Cho), creatine (Cr), and N-acetylaspartate (NAA), as well as Cho/NAA, Cho/Cr, and NAA/Cr ratio maps. Automated segmentation was achieved by concomitantly considering sMRI metabolite maps with standard contrast enhancing (CE) imaging in a pipeline that first uses the watermore » signal for skull stripping. Subsequently, an initial blob of tumor region is identified by searching for regions of FLAIR abnormalities that also display reduced NAA activity using a mean ratio correlation and morphological filters. These regions are used as starting point for a geodesic level-set refinement that adapts the initial blob to the fine details specific to each metabolite. Results: Accuracy of the segmentation model was tested on a cohort of 12 patients that had sMRI datasets acquired pre, mid and post-treatment, providing a broad range of enhancement patterns. Compared to classical imaging, where heterogeneity in the tumor appearance and shape across posed a greater challenge to the algorithm, sMRI’s regions of abnormal activity were easily detected in the sMRI metabolite maps when combining the detail available in the standard imaging with the local enhancement produced by the metabolites. Results can be imported in the treatment planning, leading in general increase in the target volumes (GTV60) when using sMRI+CE MRI compared to the standard CE MRI alone. Conclusion: Integration of automated segmentation of sMRI metabolite maps into planning is feasible and will likely streamline acceptance

  12. Volumetric Spectroscopic Imaging of Glioblastoma Multiforme Radiation Treatment Volumes

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

    Parra, N. Andres; Maudsley, Andrew A.; Gupta, Rakesh K.

    Purpose: Magnetic resonance (MR) imaging and computed tomography (CT) are used almost exclusively in radiation therapy planning of glioblastoma multiforme (GBM), despite their well-recognized limitations. MR spectroscopic imaging (MRSI) can identify biochemical patterns associated with normal brain and tumor, predominantly by observation of choline (Cho) and N-acetylaspartate (NAA) distributions. In this study, volumetric 3-dimensional MRSI was used to map these compounds over a wide region of the brain and to evaluate metabolite-defined treatment targets (metabolic tumor volumes [MTV]). Methods and Materials: Volumetric MRSI with effective voxel size of ∼1.0 mL and standard clinical MR images were obtained from 19 GBM patients.more » Gross tumor volumes and edema were manually outlined, and clinical target volumes (CTVs) receiving 46 and 60 Gy were defined (CTV{sub 46} and CTV{sub 60}, respectively). MTV{sub Cho} and MTV{sub NAA} were constructed based on volumes with high Cho and low NAA relative to values estimated from normal-appearing tissue. Results: The MRSI coverage of the brain was between 70% and 76%. The MTV{sub NAA} were almost entirely contained within the edema, and the correlation between the 2 volumes was significant (r=0.68, P=.001). In contrast, a considerable fraction of MTV{sub Cho} was outside of the edema (median, 33%) and for some patients it was also outside of the CTV{sub 46} and CTV{sub 60}. These untreated volumes were greater than 10% for 7 patients (37%) in the study, and on average more than one-third (34.3%) of the MTV{sub Cho} for these patients were outside of CTV{sub 60}. Conclusions: This study demonstrates the potential usefulness of whole-brain MRSI for radiation therapy planning of GBM and revealed that areas of metabolically active tumor are not covered by standard RT volumes. The described integration of MTV into the RT system will pave the way to future clinical trials investigating outcomes in patients treated based

  13. Early detection of secondary damage in ipsilateral thalamus after acute infarction at unilateral corona radiata by diffusion tensor imaging and magnetic resonance spectroscopy

    PubMed Central

    2011-01-01

    Background Traditional magnetic resonance (MR) imaging can identify abnormal changes in ipsilateral thalamus in patients with unilateral middle cerebral artery (MCA) infarcts. However, it is difficult to demonstrate these early changes quantitatively. Diffusion tensor imaging (DTI) and proton magnetic resonance spectroscopy (MRS) are potentially sensitive and quantitative methods of detection in examining changes of tissue microstructure and metabolism. In this study, We used both DTI and MRS to examine possible secondary damage of thalamus in patients with corona radiata infarction. Methods Twelve patients with unilateral corona radiata infarction underwent MR imaging including DTI and MRS at one week (W1), four weeks (W4), and twelve weeks (W12) after onset of stroke. Twelve age-matched controls were imaged. Mean diffusivity (MD), fractional anisotropy (FA), N-acetylaspartate (NAA), choline(Cho), and creatine(Cr) were measured in thalami. Results T1-weighted fluid attenuation inversion recovery (FLAIR), T2-weighted, and T2-FLAIR imaging showed an infarct at unilateral corona radiate but no other lesion in each patient brain. In patients, MD was significantly increased at W12, compared to W1 and W4 (all P< 0.05). NAA was significantly decreased at W4 compared to W1, and at W12 compared to W4 (all P< 0.05) in the ipsilateral thalamus. There was no significant change in FA, Cho, or Cr in the ipsilateral thalamus from W1 to W12. Spearman's rank correlation analysis revealed a significant negative correlation between MD and the peak area of NAA, Cho, and Cr at W1, W4, and W12 and a significant positive correlation of FA with NAA at W1. Conclusions These findings indicate that DTI and MRS can detect the early changes indicating secondary damage in the ipsilateral thalamus after unilateral corona radiata infarction. MRS may reveal the progressive course of damage in the ipsilateral thalamus over time. PMID:21542942

  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. 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.

  16. 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

  17. 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.

  18. The ratio of N-acetyl aspartate to glutamate correlates with disease duration of amyotrophic lateral sclerosis.

    PubMed

    Sako, Wataru; Abe, Takashi; Izumi, Yuishin; Harada, Masafumi; Kaji, Ryuji

    2016-05-01

    Glutamate (Glu)-induced excitotoxicity has been implicated in the neuronal loss of amyotrophic lateral sclerosis. To test the hypothesis that Glu in the primary motor cortex contributes to disease severity and/or duration, the Glu level was investigated using MR spectroscopy. Seventeen patients with amyotrophic lateral sclerosis were diagnosed according to the El Escorial criteria for suspected, possible, probable or definite amyotrophic lateral sclerosis, and enrolled in this cross-sectional study. We measured metabolite concentrations, including N-acetyl aspartate (NAA), creatine, choline, inositol, Glu and glutamine, and performed partial correlation between each metabolite concentration or NAA/Glu ratio and disease severity or duration using age as a covariate. Considering our hypothesis that Glu is associated with neuronal cell death in amyotrophic lateral sclerosis, we investigated the ratio of NAA to Glu, and found a significant correlation between NAA/Glu and disease duration (r=-0.574, p=0.02). The "suspected" amyotrophic lateral sclerosis patients showed the same tendency as possible, probable and definite amyotrophic lateral sclerosis patients in regard to correlation of NAA/Glu ratio with disease duration. The other metabolites showed no significant correlation. Our findings suggested that glutamatergic neurons are less vulnerable compared to other neurons and this may be because inhibitory receptors are mainly located presynaptically, which supports the notion of Glu-induced excitotoxicity. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. 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

  20. Increased myo-inositol level in dorsolateral prefrontal cortex in migraine patients with major depression.

    PubMed

    Lirng, Jiing-Feng; Chen, Hung-Chieh; Fuh, Jong-Ling; Tsai, Chia-Fen; Liang, Jen-Feng; Wang, Shuu-Jiun

    2015-07-01

    Although the comorbidity between migraine and major depressive disorder (MDD) has been recognized, the pathophysiology remains unclear. The dorsolateral prefrontal cortex (DLPFC) is a well-known neural substrate for MDD. We investigated the relationship between brain metabolites in DLPFC and comorbid MDD in migraine patients. We recruited migraine patients from a tertiary headache clinic. A board-certified psychiatrist conducted a structured interview for MDD diagnosis. The severity of depression was evaluated by the Beck Depression Inventory (BDI). Thirty migraine patients (five men, 25 women; mean age: 40.4 ± 12.4 years) completed the study, and 16 of them were diagnosed with MDD. All patients underwent a magnetic resonance spectroscopy (MRS) examination focusing on bilateral DLPFC. The ratios of N-acetylaspartate (NAA), choline (Cho), and myo-inositol (mI) to total creatine (tCr) were compared between migraine patients with and without MDD, and were correlated with BDI scores. Relative to patients without MDD, migraine patients with MDD had higher mI/tCr ratios in the bilateral DLPFC (p = 0.02, left; p = 0.02, right, Mann-Whitney U test). The mI/tCr ratios in the right DLPFC were positively correlated with BDI scores (r = 0.52, p = 0.003). The NAA/tCr and Cho/tCr ratios did not differ between migraine patients with and without MDD. Increased mI/tCr within the DLPFC might be associated with the presence of MDD in migraine patients. © International Headache Society 2014.

  1. Magnetic resonance spectroscopy of fiber tracts in children with traumatic brain injury: A combined MRS - Diffusion MRI study.

    PubMed

    Dennis, Emily L; Babikian, Talin; Alger, Jeffry; Rashid, Faisal; Villalon-Reina, Julio E; Jin, Yan; Olsen, Alexander; Mink, Richard; Babbitt, Christopher; Johnson, Jeffrey; Giza, Christopher C; Thompson, Paul M; Asarnow, Robert F

    2018-05-10

    Traumatic brain injury can cause extensive damage to the white matter (WM) of the brain. These disruptions can be especially damaging in children, whose brains are still maturing. Diffusion magnetic resonance imaging (dMRI) is the most commonly used method to assess WM organization, but it has limited resolution to differentiate causes of WM disruption. Magnetic resonance spectroscopy (MRS) yields spectra showing the levels of neurometabolites that can indicate neuronal/axonal health, inflammation, membrane proliferation/turnover, and other cellular processes that are on-going post-injury. Previous analyses on this dataset revealed a significant division within the msTBI patient group, based on interhemispheric transfer time (IHTT); one subgroup of patients (TBI-normal) showed evidence of recovery over time, while the other showed continuing degeneration (TBI-slow). We combined dMRI with MRS to better understand WM disruptions in children with moderate-severe traumatic brain injury (msTBI). Tracts with poorer WM organization, as shown by lower FA and higher MD and RD, also showed lower N-acetylaspartate (NAA), a marker of neuronal and axonal health and myelination. We did not find lower NAA in tracts with normal WM organization. Choline, a marker of inflammation, membrane turnover, or gliosis, did not show such associations. We further show that multi-modal imaging can improve outcome prediction over a single modality, as well as over earlier cognitive function measures. Our results suggest that demyelination plays an important role in WM disruption post-injury in a subgroup of msTBI children and indicate the utility of multi-modal imaging. © 2018 Wiley Periodicals, Inc.

  2. 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

  3. 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.

  4. 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

  5. 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.

  6. Machine Learning Approach for Classifying Multiple Sclerosis Courses by Combining Clinical Data with Lesion Loads and Magnetic Resonance Metabolic Features.

    PubMed

    Ion-Mărgineanu, Adrian; Kocevar, Gabriel; Stamile, Claudio; Sima, Diana M; Durand-Dubief, Françoise; Van Huffel, Sabine; Sappey-Marinier, Dominique

    2017-01-01

    Purpose: The purpose of this study is classifying multiple sclerosis (MS) patients in the four clinical forms as defined by the McDonald criteria using machine learning algorithms trained on clinical data combined with lesion loads and magnetic resonance metabolic features. Materials and Methods: Eighty-seven MS patients [12 Clinically Isolated Syndrome (CIS), 30 Relapse Remitting (RR), 17 Primary Progressive (PP), and 28 Secondary Progressive (SP)] and 18 healthy controls were included in this study. Longitudinal data available for each MS patient included clinical (e.g., age, disease duration, Expanded Disability Status Scale), conventional magnetic resonance imaging and spectroscopic imaging. We extract N -acetyl-aspartate (NAA), Choline (Cho), and Creatine (Cre) concentrations, and we compute three features for each spectroscopic grid by averaging metabolite ratios (NAA/Cho, NAA/Cre, Cho/Cre) over good quality voxels. We built linear mixed-effects models to test for statistically significant differences between MS forms. We test nine binary classification tasks on clinical data, lesion loads, and metabolic features, using a leave-one-patient-out cross-validation method based on 100 random patient-based bootstrap selections. We compute F1-scores and BAR values after tuning Linear Discriminant Analysis (LDA), Support Vector Machines with gaussian kernel (SVM-rbf), and Random Forests. Results: Statistically significant differences were found between the disease starting points of each MS form using four different response variables: Lesion Load, NAA/Cre, NAA/Cho, and Cho/Cre ratios. Training SVM-rbf on clinical and lesion loads yields F1-scores of 71-72% for CIS vs. RR and CIS vs. RR+SP, respectively. For RR vs. PP we obtained good classification results (maximum F1-score of 85%) after training LDA on clinical and metabolic features, while for RR vs. SP we obtained slightly higher classification results (maximum F1-score of 87%) after training LDA and SVM-rbf on

  7. 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.

  8. 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.

  9. hNaa10p contributes to tumorigenesis by facilitating DNMT1-mediated tumor suppressor gene silencing

    PubMed Central

    Lee, Chung-Fan; Ou, Derick S.-C.; Lee, Sung-Bau; Chang, Liang-Hao; Lin, Ruo-Kai; Li, Ying-Shiuan; Upadhyay, Anup K.; Cheng, Xiaodong; Wang, Yi-Ching; Hsu, Han-Shui; Hsiao, Michael; Wu, Cheng-Wen; Juan, Li-Jung

    2010-01-01

    Hypermethylation-mediated tumor suppressor gene silencing plays a crucial role in tumorigenesis. Understanding its underlying mechanism is essential for cancer treatment. Previous studies on human N-α-acetyltransferase 10, NatA catalytic subunit (hNaa10p; also known as human arrest-defective 1 [hARD1]), have generated conflicting results with regard to its role in tumorigenesis. Here we provide multiple lines of evidence indicating that it is oncogenic. We have shown that hNaa10p overexpression correlated with poor survival of human lung cancer patients. In vitro, enforced expression of hNaa10p was sufficient to cause cellular transformation, and siRNA-mediated depletion of hNaa10p impaired cancer cell proliferation in colony assays and xenograft studies. The oncogenic potential of hNaa10p depended on its interaction with DNA methyltransferase 1 (DNMT1). Mechanistically, hNaa10p positively regulated DNMT1 enzymatic activity by facilitating its binding to DNA in vitro and its recruitment to promoters of tumor suppressor genes, such as E-cadherin, in vivo. Consistent with this, interaction between hNaa10p and DNMT1 was required for E-cadherin silencing through promoter CpG methylation, and E-cadherin repression contributed to the oncogenic effects of hNaa10p. Together, our data not only establish hNaa10p as an oncoprotein, but also reveal that it contributes to oncogenesis through modulation of DNMT1 function. PMID:20592467

  10. 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.

  11. NAA thinning of ‘W. Murcott’

    USDA-ARS?s Scientific Manuscript database

    This study was conducted to determine if NAA thinning may be useful for managing cropload in Florida ‘W Murcott’. Trials were conducted in two groves of ages 4 and 6 years. NAA was applied on 13 May, 2010, when fruitlets averaged 10-12 mm in diameter. A randomized complete block design was used, ...

  12. 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

  13. 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.

  14. Relationship of executive functioning deficits to N-acetyl aspartate (NAA) and gamma-aminobutyric acid (GABA) in youth with bipolar disorder.

    PubMed

    Huber, Rebekah S; Kondo, Douglas G; Shi, Xian-Feng; Prescot, Andrew P; Clark, Elaine; Renshaw, Perry F; Yurgelun-Todd, Deborah A

    2018-01-01

    Although cognitive deficits in bipolar disorder (BD) have been repeatedly observed, our understanding of these impairments at a mechanistic level remains limited. Few studies that investigated cognitive impairments in bipolar illness have examined the association with brain biochemistry. This pilot study utilized proton magnetic resonance spectroscopy ( 1 H-MRS) to evaluate the relationship between neurocognitive performance and brain metabolites in youth with BD. Thirty participants, twenty depressed BD participants and ten healthy comparison participants, ages 13-21, completed mood and executive function measures. 1 H-MRS data were also acquired from the anterior cingulate cortex (ACC) using two-dimensional (2D) J-resolved 1 H-MRS sequence. Proton metabolites including N-acetyl aspartate (NAA) and gamma-aminobutyric acid (GABA) were quantified for both groups. Participants with BD performed significantly lower on executive functioning measures than comparison participants. There were significant positive correlations between Wisconsin Card Sorting Test (WCST) performance and NAA (p < .001) and GABA (p < .01) in the ACC in bipolar youth, such that as WCST performance increased, both NAA and GABA levels increased. Small sample size and lack of control for medications. These findings build on previous observations of biochemical alterations associated with BD and indicate that executive functioning deficits in bipolar youth are correlated with NAA and GABA. These results suggest that cognitive deficits occur early in the course of illness and may reflect risk factors associated with altered neurochemistry. Further investigation of the relationship between brain metabolites and cognition in BD may lead to important information for developing novel, targeted interventions. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Investigation of NAA and NAAG dynamics underlying visual stimulation using MEGA-PRESS in a functional MRS experiment

    PubMed Central

    Landim, Ricardo C.G.; Edden, Richard A.E.; Foerster, Bernd; Li, Li Min; Covolan, Roberto J.M.; Castellano, Gabriela

    2017-01-01

    N-acetyl-aspartate (NAA) is responsible for the majority of the most prominent peak in 1H-MR spectra, and has been used as diagnostic marker for several pathologies. However, ~10% of this peak can be attributed to N-acetyl-aspartyl-glutamate (NAAG), a neuropeptide whose release may be triggered by intense neuronal activation. Separate measurement of NAA and NAAG using MRS is difficult due to large superposition of their spectra. Specifically, in functional MRS (fMRS) experiments, most work has evaluated the sum NAA + NAAG, which does not appear to change during experiments. The aim of this work was to design and perform an fMRS experiment using visual stimulation and a spectral editing sequence, MEGA-PRESS, to further evaluate the individual dynamics of NAA and NAAG during brain activation. The functional paradigm used consisted of three blocks, starting with a rest (baseline) block of 320 s, followed by a stimulus block (640 s) and a rest block (640 s). Twenty healthy subjects participated in this study. On average, subjects followed a pattern of NAA decrease and NAAG increase during stimulation, with a tendency to return to basal levels at the end of the paradigm, with a peak NAA decrease of −(21 ± 19)% and a peak NAAG increase of (64 ± 62)% (Wilcoxon test, p < 0.05). These results may relate to: 1) the only known NAAG synthesis pathway is from NAA and glutamate; 2) a relationship between NAAG and the BOLD response. PMID:26656908

  16. Investigation of NAA and NAAG dynamics underlying visual stimulation using MEGA-PRESS in a functional MRS experiment.

    PubMed

    Landim, Ricardo C G; Edden, Richard A E; Foerster, Bernd; Li, Li Min; Covolan, Roberto J M; Castellano, Gabriela

    2016-04-01

    N-acetyl-aspartate (NAA) is responsible for the majority of the most prominent peak in (1)H-MR spectra, and has been used as diagnostic marker for several pathologies. However, ~10% of this peak can be attributed to N-acetyl-aspartyl-glutamate (NAAG), a neuropeptide whose release may be triggered by intense neuronal activation. Separate measurement of NAA and NAAG using MRS is difficult due to large superposition of their spectra. Specifically, in functional MRS (fMRS) experiments, most work has evaluated the sum NAA+NAAG, which does not appear to change during experiments. The aim of this work was to design and perform an fMRS experiment using visual stimulation and a spectral editing sequence, MEGA-PRESS, to further evaluate the individual dynamics of NAA and NAAG during brain activation. The functional paradigm used consisted of three blocks, starting with a rest (baseline) block of 320 s, followed by a stimulus block (640 s) and a rest block (640 s). Twenty healthy subjects participated in this study. On average, subjects followed a pattern of NAA decrease and NAAG increase during stimulation, with a tendency to return to basal levels at the end of the paradigm, with a peak NAA decrease of -(21±19)% and a peak NAAG increase of (64±62)% (Wilcoxon test, p<0.05). These results may relate to: 1) the only known NAAG synthesis pathway is from NAA and glutamate; 2) a relationship between NAAG and the BOLD response. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. 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

  18. 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.

  19. Multivariate Associations of Fluid Intelligence and NAA.

    PubMed

    Nikolaidis, Aki; Baniqued, Pauline L; Kranz, Michael B; Scavuzzo, Claire J; Barbey, Aron K; Kramer, Arthur F; Larsen, Ryan J

    2017-04-01

    Understanding the neural and metabolic correlates of fluid intelligence not only aids scientists in characterizing cognitive processes involved in intelligence, but it also offers insight into intervention methods to improve fluid intelligence. Here we use magnetic resonance spectroscopic imaging (MRSI) to measure N-acetyl aspartate (NAA), a biochemical marker of neural energy production and efficiency. We use principal components analysis (PCA) to examine how the distribution of NAA in the frontal and parietal lobes relates to fluid intelligence. We find that a left lateralized frontal-parietal component predicts fluid intelligence, and it does so independently of brain size, another significant predictor of fluid intelligence. These results suggest that the left motor regions play a key role in the visualization and planning necessary for spatial cognition and reasoning, and we discuss these findings in the context of the Parieto-Frontal Integration Theory of intelligence. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  20. 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.

  1. 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

  2. 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

  3. Maturation of limbic regions in Asperger syndrome: a preliminary study using proton magnetic resonance spectroscopy and structural magnetic resonance imaging.

    PubMed

    O'Brien, Finian M; Page, Lisa; O'Gorman, Ruth L; Bolton, Patrick; Sharma, Ajay; Baird, Gillian; Daly, Eileen; Hallahan, Brian; Conroy, Ronán M; Foy, Catherine; Curran, Sarah; Robertson, Dene; Murphy, Kieran C; Murphy, Declan G M

    2010-11-30

    People with autistic spectrum disorders (ASD, including Asperger syndrome) may have developmental abnormalities in the amygdala-hippocampal complex (AHC). However, in vivo, age-related comparisons of both volume and neuronal integrity of the AHC have not yet been carried out in people with Asperger syndrome (AS) versus controls. We compared structure and metabolic activity of the right AHC of 22 individuals with AS and 22 healthy controls aged 10-50 years and examined the effects of age between groups. We used structural magnetic resonance imaging (sMRI) to measure the volume of the AHC, and magnetic resonance spectroscopy ((1)H-MRS) to measure concentrations of N-acetyl aspartate (NAA), creatine+phosphocreatine (Cr+PCr), myo-inositol (mI) and choline (Cho). The bulk volume of the amygdala and the hippocampus did not differ significantly between groups, but there was a significant difference in the effect of age on the hippocampus in controls. Compared with controls, young (but not older) people with AS had a significantly higher AHC concentration of NAA and a significantly higher NAA/Cr ratio. People with AS, but not controls, had a significant age-related reduction in NAA and the NAA/Cr ratio. Also, in people with AS, but not controls, there was a significant relationship between concentrations of choline and age so that choline concentrations reduced with age. We therefore suggest that people with AS have significant differences in neuronal and lipid membrane integrity and maturation of the AHC. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  4. 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

  5. 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.

  6. 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.

  7. 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.

  8. 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

  9. 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 ...

  10. Occipital cortical proton MRS at 4 Tesla in human moderate MDMA polydrug users

    PubMed Central

    Cowan, Ronald L.; Bolo, Nicolas R.; Dietrich, Mary; Haga, Erica; Lukas, Scott E.; Renshaw, Perry F.

    2007-01-01

    The recreational drug MDMA (3,4, methylenedioxymethamphetamine; sold under the street name of Ecstasy) is toxic to serotonergic axons in some animal models of MDMA administration. In humans, MDMA use is associated with alterations in markers of brain function that are pronounced in occipital cortex. Among neuroimaging methods, magnetic resonance spectroscopy (MRS) studies of brain metabolites N-acetylaspartate (NAA) and myoinositol (MI) at a field strength of 1.5 Tesla (T) reveal inconsistent results in MDMA users. Because higher field strength proton MRS has theoretical advantages over lower field strengths, we used proton MRS at 4.0 T to study absolute concentrations of occipital cortical NAA and MI in a cohort of moderate MDMA users (n = 9) versus non-MDMA using (n = 7) controls. Mean NAA in non-MDMA users was 10.47 mM (± 2.51), versus 9.83 mM (± 1.94) in MDMA users. Mean MI in non-MDMA users was 7.43 mM (± 1.68), versus 6.57 mM (± 1.59) in MDMA users. There were no statistical differences in absolute metabolite levels for NAA and MI in occipital cortex of MDMA users and controls. These findings are not supportive of MDMA-induced alterations in NAA or MI levels in this small sample of moderate MDMA users. Limitations to this study suggest caution in the interpretation of these results. PMID:17574394

  11. Occipital cortical proton MRS at 4 Tesla in human moderate MDMA polydrug users.

    PubMed

    Cowan, Ronald L; Bolo, Nicolas R; Dietrich, Mary; Haga, Erica; Lukas, Scott E; Renshaw, Perry F

    2007-08-15

    The recreational drug MDMA (3,4, methylenedioxymethamphetamine; sold under the street name of Ecstasy) is toxic to serotonergic axons in some animal models of MDMA administration. In humans, MDMA use is associated with alterations in markers of brain function that are pronounced in occipital cortex. Among neuroimaging methods, magnetic resonance spectroscopy (MRS) studies of brain metabolites N-acetylaspartate (NAA) and myoinositol (MI) at a field strength of 1.5 Tesla (T) reveal inconsistent results in MDMA users. Because higher field strength proton MRS has theoretical advantages over lower field strengths, we used proton MRS at 4.0 T to study absolute concentrations of occipital cortical NAA and MI in a cohort of moderate MDMA users (n=9) versus non-MDMA using (n=7) controls. Mean NAA in non-MDMA users was 10.47 mM (+/-2.51), versus 9.83 mM (+/-1.94) in MDMA users. Mean MI in non-MDMA users was 7.43 mM (+/-.68), versus 6.57 mM (+/-1.59) in MDMA users. There were no statistical differences in absolute metabolite levels for NAA and MI in occipital cortex of MDMA users and controls. These findings are not supportive of MDMA-induced alterations in NAA or MI levels in this small sample of moderate MDMA users. Limitations to this study suggest caution in the interpretation of these results.

  12. Simultaneous measurement of Aspartate, NAA, and NAAG using HERMES spectral editing at 3 Tesla.

    PubMed

    Chan, Kimberly L; Saleh, Muhammad G; Oeltzschner, Georg; Barker, Peter B; Edden, Richard A E

    2017-07-15

    It has previously been shown that the HERMES method ('Hadamard Encoding and Reconstruction of MEGA-Edited Spectroscopy') can be used to simultaneously edit pairs of metabolites (such as N-acetyl-aspartate (NAA) and N-acetyl aspartyl glutamate (NAAG), or glutathione and GABA). In this study, HERMES is extended for the simultaneous editing of three overlapping signals, and illustrated for the example of NAA, NAAG and Aspartate (Asp). Density-matrix simulations were performed in order to optimize the HERMES sequence. The method was tested in NAA and Asp phantoms, and applied to the centrum semiovale of the nine healthy control subjects that were scanned at 3T. Both simulations and phantom experiments showed similar metabolite multiplet patterns with good segregation of all three metabolites. In vivo measurements show consistent relative signal intensities and multiplet patterns with concentrations in agreement with literature values. Simulations indicate co-editing of glutathione, glutamine, and glutamate, but their signals do not significantly overlap with the detected aspartyl resonances. This study demonstrates that a four-step Hadamard-encoded editing scheme can be used to simultaneously edit three otherwise overlapping metabolites, and can measure NAA, NAAG, and Asp in vivo in the brain at 3T with minimal crosstalk. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. On the nature of the NAA diffusion attenuated MR signal in the central nervous system.

    PubMed

    Kroenke, Christopher D; Ackerman, Joseph J H; Yablonskiy, Dmitriy A

    2004-11-01

    In the brain, on a macroscopic scale, diffusion of the intraneuronal constituent N-acetyl-L-aspartate (NAA) appears to be isotropic. In contrast, on a microscopic scale, NAA diffusion is likely highly anisotropic, with displacements perpendicular to neuronal fibers being markedly hindered, and parallel displacements less so. In this report we first substantiate that local anisotropy influences NAA diffusion in vivo by observing differing diffusivities parallel and perpendicular to human corpus callosum axonal fibers. We then extend our measurements to large voxels within rat brains. As expected, the macroscopic apparent diffusion coefficient (ADC) of NAA is practically isotropic due to averaging of the numerous and diverse fiber orientations. We demonstrate that the substantially non-monoexponential diffusion-mediated MR signal decay vs. b value can be quantitatively explained by a theoretical model of NAA confined to an ensemble of differently oriented neuronal fibers. On the microscopic scale, NAA diffusion is found to be strongly anisotropic, with displacements occurring almost exclusively parallel to the local fiber axis. This parallel diffusivity, ADCparallel, is 0.36 +/- 0.01 microm2/ms, and ADCperpendicular is essentially zero. From ADCparallel the apparent viscosity of the neuron cytoplasm is estimated to be twice as large as that of a temperature-matched dilute aqueous solution. (c) 2004 Wiley-Liss, Inc.

  14. 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

  15. 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

  16. 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.

  17. Relationship between Proton Magnetic Resonance Spectroscopy of Frontoinsular Gray Matter and Neurodevelopmental Outcomes in Very Low Birth Weight Children at the Age of 4.

    PubMed

    Durlak, Wojciech; Herman-Sucharska, Izabela; Urbanik, Andrzej; Klimek, Małgorzata; Karcz, Paulina; Dutkowska, Grażyna; Nitecka, Magdalena; Kwinta, Przemko

    2016-01-01

    Very low birth weight is associated with long term neurodevelopmental complications. Macroscopic brain abnormalities in prematurity survivors have been investigated in several studies. However, there is limited data regarding local cerebral metabolic status and neurodevelopmental outcomes. The purpose of this study was to characterize the relationship between proton magnetic resonance spectra in basal ganglia, frontal white matter and frontoinsular gray matter, neurodevelopmental outcomes assessed with the Leiter scale and the Developmental Test of Visual Perception and selected socioeconomic variables in a cohort of very low birth weight children at the age of four. Children were divided in three groups based on the severity of neurodevelopmental impairment. There were no differences in spectroscopy in basal ganglia and frontal white matter between the groups. Lower concentrations of N-acetylaspartate (NAA), choline (Cho) and myoinositol (mI) were observed in the frontoinsular cortex of the left hemisphere in children with neurodevelopmental impairment compared to children with normal neurodevelopmental outcomes. Higher parental education, daycare attendance and breastfeeding after birth were associated with more favorable neurodevelopmental prognosis, whereas rural residence was more prevalent in children with moderate and severe impairment. Our study demonstrates the role of long term neurometabolic disruption in the left frontoinsular cortex and selected socioeconomic variables in determination of neurodevelopmental prognosis in prematurity survivors.

  18. 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.

  19. 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.

  20. 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.

  1. 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.

  2. 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.

  3. Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies.

    PubMed

    Cheng, Hanyin; Dharmadhikari, Avinash V; Varland, Sylvia; Ma, Ning; Domingo, Deepti; Kleyner, Robert; Rope, Alan F; Yoon, Margaret; Stray-Pedersen, Asbjørg; Posey, Jennifer E; Crews, Sarah R; Eldomery, Mohammad K; Akdemir, Zeynep Coban; Lewis, Andrea M; Sutton, Vernon R; Rosenfeld, Jill A; Conboy, Erin; Agre, Katherine; Xia, Fan; Walkiewicz, Magdalena; Longoni, Mauro; High, Frances A; van Slegtenhorst, Marjon A; Mancini, Grazia M S; Finnila, Candice R; van Haeringen, Arie; den Hollander, Nicolette; Ruivenkamp, Claudia; Naidu, Sakkubai; Mahida, Sonal; Palmer, Elizabeth E; Murray, Lucinda; Lim, Derek; Jayakar, Parul; Parker, Michael J; Giusto, Stefania; Stracuzzi, Emanuela; Romano, Corrado; Beighley, Jennifer S; Bernier, Raphael A; Küry, Sébastien; Nizon, Mathilde; Corbett, Mark A; Shaw, Marie; Gardner, Alison; Barnett, Christopher; Armstrong, Ruth; Kassahn, Karin S; Van Dijck, Anke; Vandeweyer, Geert; Kleefstra, Tjitske; Schieving, Jolanda; Jongmans, Marjolijn J; de Vries, Bert B A; Pfundt, Rolph; Kerr, Bronwyn; Rojas, Samantha K; Boycott, Kym M; Person, Richard; Willaert, Rebecca; Eichler, Evan E; Kooy, R Frank; Yang, Yaping; Wu, Joseph C; Lupski, James R; Arnesen, Thomas; Cooper, Gregory M; Chung, Wendy K; Gecz, Jozef; Stessman, Holly A F; Meng, Linyan; Lyon, Gholson J

    2018-05-03

    N-alpha-acetylation is a common co-translational protein modification that is essential for normal cell function in humans. We previously identified the genetic basis of an X-linked infantile lethal Mendelian disorder involving a c.109T>C (p.Ser37Pro) missense variant in NAA10, which encodes the catalytic subunit of the N-terminal acetyltransferase A (NatA) complex. The auxiliary subunit of the NatA complex, NAA15, is the dimeric binding partner for NAA10. Through a genotype-first approach with whole-exome or genome sequencing (WES/WGS) and targeted sequencing analysis, we identified and phenotypically characterized 38 individuals from 33 unrelated families with 25 different de novo or inherited, dominantly acting likely gene disrupting (LGD) variants in NAA15. Clinical features of affected individuals with LGD variants in NAA15 include variable levels of intellectual disability, delayed speech and motor milestones, and autism spectrum disorder. Additionally, mild craniofacial dysmorphology, congenital cardiac anomalies, and seizures are present in some subjects. RNA analysis in cell lines from two individuals showed degradation of the transcripts with LGD variants, probably as a result of nonsense-mediated decay. Functional assays in yeast confirmed a deleterious effect for two of the LGD variants in NAA15. Further supporting a mechanism of haploinsufficiency, individuals with copy-number variant (CNV) deletions involving NAA15 and surrounding genes can present with mild intellectual disability, mild dysmorphic features, motor delays, and decreased growth. We propose that defects in NatA-mediated N-terminal acetylation (NTA) lead to variable levels of neurodevelopmental disorders in humans, supporting the importance of the NatA complex in normal human development. Copyright © 2018 American Society of Human Genetics. All rights reserved.

  4. 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

  5. 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

  6. 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.

  7. 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

  8. MR Spectroscopy to Distinguish between Supratentorial Intraventricular Subependymoma and Central Neurocytoma.

    PubMed

    Ueda, Fumiaki; Aburano, Hiroyuki; Ryu, Yasuji; Yoshie, Yuichi; Nakada, Mitsutoshi; Hayashi, Yutaka; Matsui, Osamu; Gabata, Toshifumi

    2017-07-10

    The purpose of this study was to discriminate supratentorial intraventricular subependymoma (SIS) from central neurocytoma (CNC) using magnetic resonance spectroscopy (MRS). Single-voxel proton MRS using a 1.5T or 3T MR scanner from five SISs, five CNCs, and normal controls were evaluated. They were examined using a point-resolved spectroscopy. Automatically calculated ratios comparing choline (Cho), N-acetylaspartate (NAA), myoinositol (MI), and/or glycine (Gly) to creatine (Cr) were determined. Evaluation of Cr to unsuppressed water (USW) was also performed. Mann-Whitney U test was carried out to test the significance of differences in the metabolite ratios. Detectability of lactate (Lac) and alanine (Ala) was evaluated. Although a statistically significant difference (P < 0.0001) was observed in Cho/Cr among SIS, control spectra, and CNC, no statistical difference was noted between SIS and control spectra (P = 0.11). Statistically significant differences were observed in NAA/Cr between SIS and CNC (P = 0.04) or control spectra (P < 0.0001). A statistically significant difference was observed in MI and/or Gly to Cr between SIS and control spectra (P = 0.03), and CNC and control spectra (P < 0.0006). There were no statistical differences between SIS and CNC for MI and/or Gly to Cr (P = 0.32). Significant statistical differences were found between SIS and control spectra (P < 0.0053), control spectra and CNC (P < 0.0016), and SIS and CNC (P < 0.0083) for Cr to USW. Lac inverted doublets were confirmed in two SISs. Triplets of Lac and Ala were detected in four spectra of CNC. The present study showed that MRS can be useful in discriminating SIS from CNC.

  9. Brain biochemical correlates of the plasma homocysteine level: a proton magnetic resonance spectroscopy study in the elderly subjects.

    PubMed

    Chen, Cheng-Sheng; Kuo, Yu-Ting; Tsai, Hui-Yi; Li, Chun-Wei; Lee, Chen-Chang; Yen, Cheng-Fang; Lin, Hsiu-Fen; Ko, Chih-Hung; Juo, Suh-Hang Hank; Yeh, Yi-Chun; Liu, Gin-Chung

    2011-07-01

    An elevated plasma homocysteine level has been reported to be associated with various neuropsychiatric diseases. However, little is known about the brain biochemical changes associated with the higher plasma homocysteine level. The main goal of this study was to examine the sex difference in brain biochemical concentrations using brain proton magnetic resonance spectroscopy (H MRS), and to elucidate the biochemical changes associated with plasma homocysteine levels by sex in healthy elderly subjects. Seventy elderly subjects without any clinical psychiatric and neurological disease underwent 3-T brain H MRS. MRS spectra were acquired from voxels placed on the left side of the basal ganglia, frontal lobe, and hippocampus. Brain biochemical concentrations were compared between the elderly male and female participants. Correlations between these biochemical concentrations and plasma homocysteine levels by sex were analyzed. Female participants had significantly higher levels of choline in the left frontal lobe and hippocampus, and lower creatine and myo-inositol, in the left basal ganglia than did males. A higher homocysteine level was correlated with a lower N-acetylaspartate (NAA) concentration in the left hippocampus in elderly women (r = -0.44; p = 0.03) but not in elderly men. This study found that there was a sex difference in brain biochemical concentrations in the elderly participants. A higher plasma homocysteine level was associated with a lower NAA in the hippocampus of elderly women. The sex difference in association between brain biochemical concentrations and plasma homocysteine levels needs further investigation. We speculate that after menopause, women lose protection of estrogen from the neurotoxic effects of homocysteine in the hippocampus. Future studies are required to examine this speculation.

  10. Rat strain differences in brain structure and neurochemistry in response to binge alcohol.

    PubMed

    Zahr, Natalie M; Mayer, Dirk; Rohlfing, Torsten; Hsu, Oliver; Vinco, Shara; Orduna, Juan; Luong, Richard; Bell, Richard L; Sullivan, Edith V; Pfefferbaum, Adolf

    2014-01-01

    Ventricular enlargement is a robust phenotype of the chronically dependent alcoholic human brain, yet the mechanism of ventriculomegaly is unestablished. Heterogeneous stock Wistar rats administered binge EtOH (3 g/kg intragastrically every 8 h for 4 days to average blood alcohol levels (BALs) of 250 mg/dL) demonstrate profound but reversible ventricular enlargement and changes in brain metabolites (e.g., N-acetylaspartate (NAA) and choline-containing compounds (Cho)). Here, alcohol-preferring (P) and alcohol-nonpreferring (NP) rats systematically bred from heterogeneous stock Wistar rats for differential alcohol drinking behavior were compared with Wistar rats to determine whether genetic divergence and consequent morphological and neurochemical variation affect the brain's response to binge EtOH treatment. The three rat lines were dosed equivalently and approached similar BALs. Magnetic resonance imaging and spectroscopy evaluated the effects of binge EtOH on brain. As observed in Wistar rats, P and NP rats showed decreases in NAA. Neither P nor NP rats, however, responded to EtOH intoxication with ventricular expansion or increases in Cho levels as previously noted in Wistar rats. Increases in ventricular volume correlated with increases in Cho in Wistar rats. The latter finding suggests that ventricular volume expansion is related to adaptive changes in brain cell membranes in response to binge EtOH. That P and NP rats responded differently to EtOH argues for intrinsic differences in their brain cell membrane composition. Further, differential metabolite responses to EtOH administration by rat strain implicate selective genetic variation as underlying heterogeneous effects of chronic alcoholism in the human condition.

  11. 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.

  12. Decrease of NAA with aging outside the seizure focus in mesial temporal lobe epilepsy--a proton-MRS study at 3 Tesla.

    PubMed

    Riederer, Franz; Bittsanský, Michal; Lehner-Baumgartner, Eva; Baumgartner, Christoph; Mlynárik, Vladimír; Gruber, Stephan; Moser, Ewald; Kaya, Marihan; Serles, Wolfgang

    2007-11-07

    There is evidence that chronic pharmacoresistant temporal lobe epilepsy (TLE) is a progressive disorder accompanied by mental deterioration. We investigated effects of aging on cerebral N-acetyl-aspartate (NAA) concentrations in the temporal lobe of 12 patients with pharmacoresistant mesial TLE (mTLE) and 22 healthy controls by means of proton-magnetic resonance spectroscopy ((1)H-MRS) at 3 T. Furthermore, we calculated correlations between NAA concentrations and measures of verbal and figural memory in patients. In mTLE patients but not in healthy controls the concentration of NAA in the lateral temporal lobe was negatively correlated with age. In patients with mTLE NAA in left lateral temporal voxels correlated with verbal memory. NAA in medial temporal voxels did not correlate with age or neuropsychological measures. Significant decrease of NAA with age in the lateral temporal lobe of patients with mTLE provides evidence for progressive neuronal dysfunction with aging. NAA is a marker of neuronal integrity since it correlates with verbal memory.

  13. Magnetic resonance imaging spectroscopy in pediatric atypical teratoid rhabdoid tumors of the brain.

    PubMed

    Bruggers, Carol S; Moore, Kevin

    2014-08-01

    Pediatric central nervous system (CNS) atypical teratoid rhabdoid tumors (ATRT) are highly malignant tumors characterized by SMARCB1 gene abnormalities. Despite chemoradiation responsiveness, most children die of disease. No imaging findings distinguish ATRT from other malignant brain tumors. This study sought to describe magnetic resonance spectroscopy (MRS) of childhood CNS ATRT and identify metabolite patterns for diagnosis and disease status monitoring. Data from 7 children diagnosed with CNS ATRT from 2007 to 2010, whose imaging included MRS, were retrospectively reviewed. Age at diagnosis ranged from 2.5 to 54 months. Tumors were large with calcium and cysts and avid gadolinium enhancement. All were isointense on T1-weighted imaging and mildly hyperintense on T2-weighted imaging. Short-TE MRS showed prominent lactate+lipid and choline, minimal N-acetyl acetate (NAA), and rarely minimal myoinositol and low creatine peaks. Long TE showed prominent choline, minimal NAA, and rarely low lactate peaks. The combination of prominent choline and lactate+lipids peaks, and generally absent NAA and myoinositol peaks by MRS in this panel of ATRT expands existing information and provides a potentially distinct metabolite profile from other malignant pediatric brain tumors, including medulloblastoma. Prospective, comparative quantitative MRS of ATRT with other pediatric CNS tumors is warranted.

  14. 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.

  15. 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.

  16. 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

  17. 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.

  18. 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.

  19. 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.

  20. 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

  1. 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.

  2. Brief Report: Biochemical correlates of clinical impairment in high functioning autism and Asperger’s disorder

    PubMed Central

    Kleinhans, Natalia M.; Richards, Todd; Weaver, Kurt E.; Liang, Olivia; Dawson, Geraldine; Aylward, Elizabeth

    2014-01-01

    Amygdala dysfunction has been proposed as a critical contributor to social impairment in autism spectrum disorders (ASD). The current study investigated biochemical abnormalities in the amygdala in 20 high functioning adults with autistic disorder or Asperger’s disorder and 19 typically developing adults matched on age and IQ. Magnetic resonance spectroscopy was used to measure n-acetyl aspartate (NAA), creatine/phosphocreatine (Cre), choline/choline containing compounds (Cho), and Myoinositol (mI) in the right and left amygdala. There were no significant between-group differences in any of the metabolites. However, NAA and Cre levels were significantly correlated to clinical ratings on the Autism Diagnostic Interview-Revised. This suggests that altered metabolite levels in the amygdala may be associated with a more severe early developmental course in ASD. PMID:19234776

  3. Association of brain metabolism with sulcation and corpus callosum development assessed by MRI in late-onset small fetuses.

    PubMed

    Sanz-Cortes, Magdalena; Egaña-Ugrinovic, Gabriela; Simoes, Rui V; Vazquez, Lucia; Bargallo, Nuria; Gratacos, Eduard

    2015-06-01

    We sought to determine the relationship between fetal brain metabolism and microstructure expressed by brain sulcation, and corpus callosum (CC) development assessed by fetal brain magnetic resonance (MR) imaging and proton MR spectroscopy ((1)H-MRS). A total of 119 fetuses, 64 that were small for gestational age (estimated fetal weight <10th centile and normal umbilical artery Doppler) and 55 controls underwent a 3T MR imaging/(1)H-MRS exam at 37 weeks. Anatomical T2-weighted images were obtained in the 3 orthogonal planes and long echo time (TE) (1)H-MRS acquired from the frontal lobe. Head biometrics, cortical fissure depths (insula, Sylvian, parietooccipital, cingulate, and calcarine), and CC area and biometries were blindly performed by manual and semiautomated delineation using Analyze software and corrected creating ratios for biparietal diameter and frontooccipital diameter, respectively, for group comparison. Spectroscopic data were processed using LCModel software and analyzed as metabolic ratios of N-acetylaspartate (NAA) to choline (Cho), Cho to creatine (Cr), and myo-inositol (Ino) to Cho. Differences between cases and controls were assessed. To test for the association between metabolic ratios and microstructural parameters, bivariate correlation analyses were performed. Spectroscopic findings showed decreased NAA/Cho and increased Cho/Cr ratios in small fetuses. They also presented smaller head biometrics, shorter and smaller CC, and greater insular and cingulate depths. Frontal lobe NAA/Cho significantly correlated with biparietal diameter (r = 0.268; P = .021), head circumference (r = 0.259; P = .026), CC length (r = 0.265; P = .026), CC area (r = 0.317; P = .007), and the area of 6 from the 7 CC subdivisions. It did not correlate with any of the cortical sulcation parameters evaluated. None of the other metabolic ratios presented significant correlations with cortical development or CC parameters. Frontal lobe NAA/Cho levels-which are considered a

  4. A Piglet Model for Detection of Hypoxic-Ischemic Brain Injury with Magnetic Resonance Imaging

    PubMed Central

    Munkeby, B. H.; De Lange, C.; Emblem, K. E.; Bjørnerud, A.; Kro, G. A. B.; Andresen, J.; Winther-Larssen, E. H.; Løberg, E. M.; Hald, J. K.

    2008-01-01

    Munkeby BH, de Lange C, Emblem KE, Bjørnerud A, Kro GAB, Andresen J, Winther-Larssen EH, Løberg EM, Hald JK. A piglet model for detection of hypoxic-ischemic brain injury with magnetic resonance imaging. Acta Radiol 2008;49:1049–1057. Background Early detection of hypoxic-ischemic (HI) injury in the asphyxic newborn is important because present prognostic factors are inadequate. Furthermore, therapeutic interventions may have additional benefit if initiated in time. Purpose To assess whether the use of a combined protocol including conventional magnetic resonance imaging (MRI), diffusion-weighted imaging (DWI), diffusion tensor imaging (DTI), and proton MR spectroscopy (MRS) could detect pathological findings in a piglet model 7 hours after HI. Material and Methods Ten piglets were submitted to HI for 30 min followed by reoxygenation with 21% O2 for 7 hours. MRI at 1.5T was done prior to and 7 hours after the HI. Single-voxel proton MRS was performed, and apparent diffusion coefficient (ADC) and fractional anisotropy (FA) were measured in the basal ganglia. MRS identified N-acetylaspartate (NAA), choline (Cho), creatine (Cr), and lactate (Lac). Histology and microtubule-associated protein 2 (MAP-2) staining was performed in the basal ganglia at the end of the experiment. Results Compared to baseline, ADC, NAA/Cho, and NAA/Cr were significantly reduced after 7 hours (P < 0.001, P = 00.01, and P = 00.05, respectively) and FA values were increased (P <0.025). The ratios of Lac/Cho and Lac/NAA were significantly higher after 7 hours compared to baseline (P <0.001). Presence of necrosis correlated well with reduced ADC (RS = 0.91) and presence of Lac (RS = 0.80). Histology and MAP-2 staining showed more than 90% necrosis in eight piglets, 60% in one piglet, and no necrosis in one piglet. Conclusion Diffusion MRI and proton MRS can detect HI injury in the piglet brain 7 hours after hypoxia. DWI and MRS can be used to give useful prognostic information. This piglet

  5. 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.

  6. 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.

  7. 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

  8. 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

  9. Neurodevelopmental delay with critical congenital heart disease is mainly from prenatal injury not infant cardiac surgery: current evidence based on a meta-analysis of functional magnetic resonance imaging.

    PubMed

    Li, Y; Yin, S; Fang, J; Hua, Y; Wang, C; Mu, D; Zhou, K

    2015-06-01

    No consensus has been reached regarding whether brain injury related to congenital heart disease (CHD) is caused by infant cardiac surgery and/or prenatal injury resulting from the CHD. We performed this meta-analysis to identify the likely cause of neurodevelopmental delay in CHD patients. We carried out a literature search without language restriction in December 2013, retrieving records from PubMed, EMBASE, the Cochrane Library and the World Health Organization trials center, to identify studies applying functional magnetic resonance imaging (fMRI) evaluation of brain function before surgery and, in some cases, after surgery (both immediate term and short term postoperatively). The preoperative and postoperative fMRI results were extracted, and meta-analysis was performed using Revman 5.1.1 and STATA 11.0, according to the guidelines from the Cochrane review and MOOSE groups. The electronic search yielded 937 citations. Full text was retrieved for 15 articles and eight articles (nine studies) were eligible for inclusion: six studies (n = 312 cases) with fMRI analysis before surgery and three (n = 36 cases) with complete perioperative fMRI analysis. The overall average diffusivity of CHD cases was significantly higher than that of controls, with a summarized standard (std) mean difference of 1.39 (95% CI, 0.70-2.08), and the fractional anisotropy was lower in CHD cases, with a summarized mean difference of -1.43 (95% CI, -1.95 to -0.91). N-acetylaspartate (NAA)/choline (Cho) for the whole brain was significantly lower in CHD cases compared with healthy ones, while lactate/Cho was significantly higher in CHD cases. Immediate term postoperatively, significant changes in NAA/creatine and NAA/Cho, relative to preoperative values, were found. However, the difference did not persist at the short-term follow-up. This meta-analysis suggests that the delay in neurological development in newborns with CHD is due mainly to prenatal injury, and cardiac surgery might

  10. 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.

  11. 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.

  12. 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.

  13. 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

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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

  19. 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

  20. 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.

  1. 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.

  2. 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.

  3. 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

  4. 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.

  5. Spectroscopic imaging of the pilocarpine model of human epilepsy suggests that early NAA reduction predicts epilepsy.

    PubMed

    Gomes, W A; Lado, F A; de Lanerolle, N C; Takahashi, K; Pan, C; Hetherington, H P

    2007-08-01

    Reduced hippocampal N-acetyl aspartate (NAA) is commonly observed in patients with advanced, chronic temporal lobe epilepsy (TLE). It is unclear, however, whether an NAA deficit is also present during the clinically quiescent latent period that characterizes early TLE. This question has important implications for the use of MR spectroscopic imaging (MRSI) in the early identification of patients at risk for TLE. To determine whether NAA is diminished during the latent period, we obtained high-resolution (1)H spectroscopic imaging during the latent period of the rat pilocarpine model of human TLE. We used actively detuneable surface reception and volume transmission coils to enhance sensitivity and a semiautomated voxel shifting method to accurately position voxels within the hippocampi. During the latent period, 2 and 7 d following pilocarpine treatment, hippocampal NAA was significantly reduced by 27.5 +/- 6.9% (P < 0.001) and 17.3 +/- 6.9% (P < 0.001) at 2 and 7 d, respectively. Quantitative estimates of neuronal loss at 7 d (2.3 +/- 7.7% reduction; P = 0.58, not significant) demonstrate that the NAA deficit is not due to neuron loss and therefore likely represents metabolic impairment of hippocampal neurons during the latent phase. Therefore, spectroscopic imaging provides an early marker for metabolic dysfunction in this model of TLE.

  6. 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.

  7. 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.

  8. [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.

  9. 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

  10. 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.

  11. 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...

  12. 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...

  13. 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...

  14. 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...

  15. 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...

  16. 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...

  17. 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...

  18. 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...

  19. 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...

  20. 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.

  1. 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.

  2. 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.

  3. 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

  4. 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.

  5. 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.

  6. A mild traumatic brain injury in mice produces lasting deficits in brain metabolism.

    PubMed

    Lyons, Danielle N; Vekaria, Hemendra; Macheda, Teresa; Bakshi, Vikas; Powell, David K; Gold, Brian T; Lin, Ai-Ling; Sulllivan, Pat; Bachstetter, Adam D

    2018-05-29

    Metabolic uncoupling has been well-characterized during the first minutes-to-days after a traumatic brain injury (TBI), yet mitochondrial bioenergetics during the weeks-to-months after a brain injury is poorly defined, particularly after a mild TBI. We hypothesized that a closed head injury (CHI) would be associated with deficits in mitochondrial bioenergetics at one month after the injury. A significant decrease in state-III (ATP production) and state-V (complex-I) driven mitochondrial respiration was found at 1-month post-injury in adult C57Bl/6J mice. Isolation of synaptic mitochondria demonstrated that the deficit in state-III and state-V was primarily neuronal. Injured mice had a temporally consistent deficit in memory recall at 1-month post injury. Using proton magnetic resonance spectroscopy (1H MRS) at 7-Tesla, we found significant decreases in phosphocreatine, N-Acetylaspartic acid (NAA), and total choline. We also found regional variations in cerebral blood flow, including both hypo- and hyper- perfusion, as measured by a pseudo-continuous arterial spin labeling MR sequence. Our results highlight a chronic deficit in mitochondrial bioenergetics associated with a CHI that may lead toward a novel approach for neurorestoration following a mild TBI. Magnetic resonance spectroscopy provides a potential biomarker for assessing the efficacy of candidate treatments targeted at improving mitochondrial bioenergetics.

  7. 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

  8. 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.

  9. 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.

  10. 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.

  11. Assessment of Anterior Cingulate Cortex (ACC) and Left Cerebellar Metabolism in Asperger's Syndrome with Proton Magnetic Resonance Spectroscopy (MRS).

    PubMed

    Goji, Aya; Ito, Hiromichi; Mori, Kenji; Harada, Masafumi; Hisaoka, Sonoka; Toda, Yoshihiro; Mori, Tatsuo; Abe, Yoko; Miyazaki, Masahito; Kagami, Shoji

    2017-01-01

    Proton magnetic resonance spectroscopy (1H MRS) is a noninvasive neuroimaging method to quantify biochemical metabolites in vivo and it can serve as a powerful tool to monitor neurobiochemical profiles in the brain. Asperger's syndrome (AS) is a type of autism spectrum disorder, which is characterized by impaired social skills and restrictive, repetitive patterns of interest and activities, while intellectual levels and language skills are relatively preserved. Despite clinical aspects have been well-characterized, neurometabolic profiling in the brain of AS remains to be clear. The present study used proton magnetic resonance spectroscopy (1H MRS) to investigate whether pediatric AS is associated with measurable neurometabolic abnormalities that can contribute new information on the neurobiological underpinnings of the disorder. Study participants consisted of 34 children with AS (2-12 years old; mean age 5.2 (±2.0); 28 boys) and 19 typically developed children (2-11 years old; mean age 5.6 (±2.6); 12 boys) who served as the normal control group. The 1H MRS data were obtained from two regions of interest: the anterior cingulate cortex (ACC) and left cerebellum. In the ACC, levels of N-acetylaspartate (NAA), total creatine (tCr), total choline-containing compounds (tCho) and myo-Inositol (mI) were significantly decreased in children with AS compared to controls. On the other hand, no significant group differences in any of the metabolites were found in the left cerebellum. Neither age nor sex accounted for the metabolic findings in the regions. The finding of decreased levels of NAA, tCr, tCho, and mI in the ACC but not in left cerebellar voxels in the AS, suggests a lower ACC neuronal density in the present AS cohort compared to controls.

  12. (1)H-MRS in glutaric aciduria type 1: impact of biochemical phenotype and age on the cerebral accumulation of neurotoxic metabolites.

    PubMed

    Harting, Inga; Boy, Nikolas; Heringer, Jana; Seitz, Angelika; Bendszus, Martin; Pouwels, Petra J W; Kölker, Stefan

    2015-09-01

    In glutaric aciduria type 1 (GA1) the neurotoxic metabolites glutaric acid (GA) and 3-hydroxyglutaric acid (3-OH-GA) accumulate within the brain. Due to limited efflux across the blood-brain-barrier biochemical monitoring of intracerebrally accumulating toxic metabolites is as yet not possible. To investigate brain metabolic patterns in glutaric aciduria type 1 using (1)H magnetic resonance spectroscopy ((1)H-MRS) with focus on detecting the disease-related neurotoxic metabolites GA and 3-OH-GA. Short echo time (1)H-MRS was performed in 13 treated metabolically stable patients. Twenty-one white matter and 16 basal ganglia spectra from 12 patients (age range 7 months - 22 years) were included. Subgroups based on age, biochemical phenotype and/or associated MRI changes were compared with control spectra. GA was elevated in white matter of patients. 3-OH-GA was elevated in white matter of older patients with associated signal changes on MRI, which was structurally characterized by decreased creatine and phosphocreatine (tCr) and elevated choline (Cho). Metabolite changes differed with biochemical phenotype and disease duration: Low excretors with up to 30% residual enzyme activity had only mildly, non-significantly elevated GA and mildly subnormal N-acetylaspartate (tNAA). High excretors with complete lack of enzyme activity had significantly increased GA, tNAA was mildly subnormal in younger and decreased in older high excretors. GA and 3-OH-GA are detectable by in vivo (1)H-MRS, which might finally allow biochemical follow-up monitoring of intracerebrally accumulating neurotoxic metabolites in GA1. A high excreting phenotype appears to be a risk factor for cerebral GA accumulation and progressive neuroaxonal compromise despite a similar clinical course in younger high and low excreting patients. This might have consequences for long-term outcome.

  13. 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.

  14. A Longitudinal Assessment of Structural and Chemical Alterations in Mixed Martial Arts Fighters.

    PubMed

    Mayer, Andrew R; Ling, Josef M; Dodd, Andrew B; Gasparovic, Charles; Klimaj, Stefan D; Meier, Timothy B

    2015-11-15

    Growing evidence suggests that temporally proximal acute concussions and repetitive subconcussive head injuries may lead to long-term neurological deficits. However, the underlying mechanisms of injury and their relative time-scales are not well documented in human injury models. The current study therefore investigated whether biomarkers of brain chemistry (magnetic resonance [MR] spectroscopy: N-acetylaspartate [NAA], combined glutamate and glutamine [Glx], total creatine [Cre], choline compounds [Cho], and myo-inositol [mI]) and structure (cortical thickness, white matter [WM]/subcortical volume) differed between mixed martial artists (MMA; n = 13) and matched healthy controls (HC) without a history of contact sport participation (HC; n = 14). A subset of participants (MMA = 9; HC = 10) returned for follow-up visits, with MMA (n = 3) with clinician-documented acute concussions also scanned serially. As expected, MMA self-reported a higher incidence of previous concussions and significantly more cognitive symptoms during prior concussion recovery. Fighters also exhibited reduced memory and processing speed relative to controls on neuropsychological testing coupled with cortical thinning in the left posterior cingulate gyrus and right occipital cortex at baseline assessment. Over a 1-year follow-up period, MMA experienced a significant decrease in both WM volume and NAA concentration, as well as relative thinning in the left middle and superior frontal gyri. These longitudinal changes did not correlate with self-reported metrics of injury (i.e., fight diary). In contrast, HC did not exhibit significant longitudinal changes over a 4-month follow-up period (p > 0.05). Collectively, current results provide preliminary evidence of progressive changes in brain chemistry and structure over a relatively short time period in individuals with high exposure to repetitive head hits. These findings require replication in independent samples.

  15. 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.

  16. APOLLO CREW (NAA) - ASTRONAUT EDWARD H. WHITE - TRAINING

    NASA Image and Video Library

    1966-06-24

    The members of the prime crew of the first manned Apollo space flight Apollo/Saturn 204 (AS-204) inspect spacecraft equipment during a tour of North American Aviation's (NAA) Downey facility. In the foreground, left to right, are astronauts Roger B. Chaffee, Virgil I. Grissom, and Edward H. White, II. NAA engineers and technicians are in the background. NORTH AMERICAN AVIATION, INC., DOWNEY, CA B&W

  17. 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.

  18. 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

  19. 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

  20. 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.

  1. 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.

  2. 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.

  3. 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

  4. N-acetyl-aspartate levels correlate with intra-axonal compartment parameters from diffusion MRI.

    PubMed

    Grossman, Elan J; Kirov, Ivan I; Gonen, Oded; Novikov, Dmitry S; Davitz, Matthew S; Lui, Yvonne W; Grossman, Robert I; Inglese, Matilde; Fieremans, Els

    2015-09-01

    Diffusion MRI combined with biophysical modeling allows for the description of a white matter (WM) fiber bundle in terms of compartment specific white matter tract integrity (WMTI) metrics, which include intra-axonal diffusivity (Daxon), extra-axonal axial diffusivity (De||), extra-axonal radial diffusivity (De┴), axonal water fraction (AWF), and tortuosity (α) of extra-axonal space. Here we derive these parameters from diffusion kurtosis imaging to examine their relationship to concentrations of global WM N-acetyl-aspartate (NAA), creatine (Cr), choline (Cho) and myo-Inositol (mI), as measured with proton MR spectroscopy ((1)H-MRS), in a cohort of 25 patients with mild traumatic brain injury (MTBI). We found statistically significant (p<0.05) positive correlations between NAA and Daxon, AWF, α, and fractional anisotropy; negative correlations between NAA and De,┴ and the overall radial diffusivity (D┴). These correlations were supported by similar findings in regional analysis of the genu and splenium of the corpus callosum. Furthermore, a positive correlation in global WM was noted between Daxon and Cr, as well as a positive correlation between De|| and Cho, and a positive trend between De|| and mI. The specific correlations between NAA, an endogenous probe of the neuronal intracellular space, and WMTI metrics related to the intra-axonal space, combined with the specific correlations of De|| with mI and Cho, both predominantly present extra-axonally, corroborate the overarching assumption of many advanced modeling approaches that diffusion imaging can disentangle between the intra- and extra-axonal compartments in WM fiber bundles. Our findings are also generally consistent with what is known about the pathophysiology of MTBI, which appears to involve both intra-axonal injury (as reflected by a positive trend between NAA and Daxon) as well as axonal shrinkage, demyelination, degeneration, and/or loss (as reflected by correlations between NAA and De

  5. 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.

  6. 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...

  7. 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

  8. 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

  9. 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...

  10. 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.

  11. 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.

  12. Effects of IBA and NAA treatments on rooting Douglas-fir stem cuttings.

    Treesearch

    D.L. Copes

    2000-01-01

    The effectiveness of six IBA and four NAA concentrations, four combinations of IBA and NAA concentrations, and control were tested for their ability to enhance rooting frequency (%) of Douglas-fir cuttings. Two IBA and one NAA treatments were also compared to the control for quality of root system. Between 1984 and 1998, six independent studies were conducted in mist...

  13. Proton magnetic resonance spectroscopy in ecstasy (MDMA) users.

    PubMed

    Daumann, Jörg; Fischermann, Thomas; Pilatus, Ulrich; Thron, Armin; Moeller-Hartmann, Walter; Gouzoulis-Mayfrank, Euphrosyne

    2004-05-20

    The popular recreational drug 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) has well-recognized neurotoxic effects upon central serotonergic systems in animal studies. In humans, the use of MDMA has been linked to cognitive problems, particularly to deficits in long-term memory and learning. Recent studies with proton magnetic resonance spectroscopy (1H MRS) have reported relatively low levels of the neuronal marker N-acetylaspartate (NAA) in MDMA users, however, these results have been ambiguous. Moreover, the only available 1H MRS study of the hippocampus reported normal findings in a small sample of five MDMA users. In the present study, we compared 13 polyvalent ecstasy users with 13 matched controls. We found no differences between the NAA/creatine/phosphocreatine (Cr) ratios of users and controls in neocortical regions, and only a tendency towards lower NAA/Cr ratios in the left hippocampus of MDMA users. Thus, compared with cognitive deficits, 1H MRS appears to be a less sensitive marker of potential neurotoxic damage in ecstasy users. Copyright 2004 Elsevier Ireland Ltd.

  14. 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

  15. 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

  16. 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.

  17. 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

  18. 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

  19. Decreased NAA in gray matter is correlated with decreased availability of acetate in white matter in postmortem multiple sclerosis cortex.

    PubMed

    Li, S; Clements, R; Sulak, M; Gregory, R; Freeman, E; McDonough, J

    2013-11-01

    Multiple sclerosis (MS) is an inflammatory neurodegenerative disease of the central nervous system (CNS) which leads to progressive neurological disability. Our previous studies have demonstrated mitochondrial involvement in MS cortical pathology and others have documented decreased levels of the neuronal mitochondrial metabolite N-acetyl aspartate (NAA) in the MS brain. While NAA is synthesized in neurons, it is broken down in oligodendrocytes into aspartate and acetate. The resulting acetate is incorporated into myelin lipids, linking neuronal mitochondrial function to oligodendrocyte-mediated elaboration of myelin lipids in the CNS. In the present study we show that treating human SH-SY5Y neuroblastoma cells with the electron transport chain inhibitor antimycin A decreased levels of NAA as measured by HPLC. To better understand the significance of the relationship between mitochondrial function and levels of NAA and its breakdown product acetate on MS pathology we then quantitated the levels of NAA and acetate in MS and control postmortem tissue blocks. Regardless of lesion status, we observed that levels of NAA were decreased 25 and 32 % in gray matter from parietal and motor cortex in MS, respectively, compared to controls. Acetate levels in adjacent white matter mirrored these decreases as evidenced by the 36 and 45 % reduction in acetate obtained from parietal and motor cortices. These data suggest a novel mechanism whereby mitochondrial dysfunction and reduced NAA levels in neurons may result in compromised myelination by oligodendrocytes due to decreased availability of acetate necessary for the synthesis of myelin lipids.

  20. 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

  1. 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.

  2. 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.

  3. 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

  4. 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.

  5. 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

  6. 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

  7. Neurochemical effects of quetiapine in patients with bipolar mania: a proton magnetic resonance spectroscopy study.

    PubMed

    Adler, Caleb M; DelBello, Melissa P; Weber, Wade A; Jarvis, Kelly B; Welge, Jeffrey; Chu, Wen-Jang; Rummelhoff, Emily; Kim, Mi-Jung; Lee, Jing-Huei; Strakowski, Stephen M

    2013-08-01

    Although the neurophysiology underlying pharmacotherapy for bipolar disorder remains poorly understood, recent studies suggest that therapeutic mechanisms may be reflected in changes in concentrations of N-acetylaspartate (NAA), a putative measure of neuronal integrity and metabolism. In this study, we used magnetic resonance spectroscopy (MRS) to examine prefrontal NAA in patients receiving quetiapine for bipolar mania. On the basis of previous findings, we hypothesized that remission would be associated with increased NAA concentrations in the prefrontal cortex. Thirty-one manic bipolar patients and 13 healthy subjects were recruited to participate in this prospective study. All subjects participated in MRS at baseline and after 8 weeks of treatment. Bipolar subjects received open-label quetiapine monotherapy (mean dose [SD], 584 [191] mg). Fourteen patients remitted (Young Mania Rating Scale ≤ 12) ("remitters"), 11 patients did not ("nonremitters"), and 6 patients were lost to follow-up. Bipolar and healthy subjects did not significantly differ in baseline NAA or degree of change during the 8 weeks. Remitters showed greater mean baseline NAA concentrations in the right ventrolateral prefrontal cortex compared with nonremitters (P < 0.05). In the anterior cingulate, remitters showed near significantly decreased baseline NAA concentrations at baseline (P < 0.06), and significant differences in NAA change during the 8 weeks of treatment (P < 0.03). Manic patients who remitted with quetiapine treatment in the course of this study exhibited distinct patterns of baseline prefrontal NAA concentration, coupled with decreased NAA in the anterior cingulate with treatment; the latter possibly reflecting disparate effects of quetiapine on neuronal metabolism. These data support suggestions that therapeutic effects of quetiapine involve metabolic effects on specific prefrontal regions.

  8. 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.

  9. 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...

  10. 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...

  11. 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...

  12. 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...

  13. 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...

  14. 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...

  15. 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...

  16. 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...

  17. 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...

  18. 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...

  19. NAA For Human Serum Analysis: Comparison With Conventional Analyses

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

    Oliveira, Laura C.; Zamboni, Cibele B.; Medeiros, Jose A. G.

    2010-08-04

    Instrumental and Comparator methods of Neutron Activation Analysis (NAA) were applied to determine elements of clinical relevancy in serum samples of adult population (Sao Paulo city, Brazil). A comparison with the conventional analyses, Colorimetric for calcium, Titrymetric for chlorine and Ion Specific Electrode for sodium and potassium determination were also performed permitting a discussion about the performance of NAA methods for clinical chemistry research.

  20. 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

  1. Proton MRS of the peritumoral brain.

    PubMed

    Chernov, Mikhail F; Kubo, Osami; Hayashi, Motohiro; Izawa, Masahiro; Maruyama, Takashi; Usukura, Masao; Ono, Yuko; Hori, Tomokatsu; Takakura, Kintomo

    2005-02-15

    Long-echo (TR: 2000 ms, TE: 136 ms) proton MRS of the cerebral tissue in the vicinity to intracranial lesion was done in 15 patients, mainly with parenchymal brain tumors. Significant decrease of N-acetylaspartate (NAA) (P<0.001) and more frequent presence of lactate (P<0.01) comparing with distant normal white matter were found in the perilesional brain tissue. The level of NAA in the perilesional brain tissue had negative associations with presence of lactate in the lesion (P<0.05), excess of lactate in the lesion compared to perilesional brain (P<0.01), grade of the perilesional edema (P<0.01) and patient's age (P<0.05). Multivariate analysis disclosed that identification of lactate in the lesion is associated with lower relative NAA content in the perilesional brain tissue, independently on the presence or absence of any other factor, including brain edema (P<0.001). In patients with lobar lesions who had at least one epileptic seizure during course of their disease the relative NAA content in the perilesional brain was significantly lower, comparing with those who were seizure-free (P<0.05). Therefore, lactate diffused from the tumor, or other metabolites secreted by lactate-producing neoplasm, should be considered as important contributors to the neuronal dysfunction in the surrounding brain. Decrease of NAA in the vicinity to intracranial lesions may reflect neuronal alteration responsible for associated epilepsy.

  2. Neurometabolic characteristics in the anterior cingulate gyrus of Alzheimer's disease patients with depression: a (1)H magnetic resonance spectroscopy study.

    PubMed

    Guo, Zhongwei; Zhang, Jiangtao; Liu, Xiaozheng; Hou, Hongtao; Cao, Yulin; Wei, Fuquan; Li, Japeng; Chen, Xingli; Shen, Yuedi; Chen, Wei

    2015-12-02

    Depression is a common comorbid psychiatric symptom in patients with Alzheimer's disease (AD), and the prevalence of depression is higher among people with AD compared with healthy older adults. Comorbid depression in AD may increase the risk of cognitive decline, impair patients' function, and reduce their quality of life. However, the mechanisms of depression in AD remain unclear. Here, our aim was to identify neurometabolic characteristics in the brain that are associated with depression in patients with mild AD. Thirty-seven patients were evaluated using the Neuropsychiatric Inventory (NPI) and Hamilton Depression Rating Scale (HAMD-17), and divided into two groups: 17 AD patients with depression (D-AD) and 20 non-depressed AD patients (nD-AD). Using proton magnetic resonance spectroscopy, we characterized neurometabolites in the anterior cingulate gyrus (ACG) of D-AD and nD-AD patients. Compared with nD-AD patients, D-AD patients showed lower N-acetylaspartate/creatine (NAA/Cr) and higher myo-inositol/creatine (mI/Cr) in the left ACG. NPI score correlated with NAA/Cr and mI/Cr in the left ACG, while HAMD correlated with NAA/Cr. Our findings show neurometabolic alterations in D-AD patients. Thus, D-AD pathogenesis may be attributed to abnormal activity of neurons and glial cells in the left ACG.

  3. Decreased NAA in Gray Matter is Correlated with Decreased Availability of Acetate in White Matter in Postmortem Multiple Sclerosis Cortex

    PubMed Central

    Li, S.; Clements, R.; Sulak, M.; Gregory, R.; Freeman, E.; McDonough, J.

    2013-01-01

    Multiple sclerosis (MS) is an inflammatory neurodegenerative disease of the central nervous system (CNS) which leads to progressive neurological disability. Our previous studies have demonstrated mitochondrial involvement in MS cortical pathology and others have documented decreased levels of the neuronal mitochondrial metabolite N-acetyl aspartate (NAA) in the MS brain. While NAA is synthesized in neurons, it is broken down in oligodendrocytes into aspartate and acetate. The resulting acetate is incorporated into myelin lipids, linking neuronal mitochondrial function to oligodendrocyte-mediated elaboration of myelin lipids in the CNS. In the present study we show that treating human SH-SY5Y neuroblastoma cells with the electron transport chain inhibitor antimycin A decreased levels of NAA as measured by HPLC. To better understand the significance of the relationship between mitochondrial function and levels of NAA and its breakdown product acetate on MS pathology we then quantitated the levels of NAA and acetate in MS and control postmortem tissue blocks. Regardless of lesion status, we observed that levels of NAA were decreased 25 and 32 % in gray matter from parietal and motor cortex in MS, respectively, compared to controls. Acetate levels in adjacent white matter mirrored these decreases as evidenced by the 36 and 45 % reduction in acetate obtained from parietal and motor cortices. These data suggest a novel mechanism whereby mitochondrial dysfunction and reduced NAA levels in neurons may result in compromised myelination by oligodendrocytes due to decreased availability of acetate necessary for the synthesis of myelin lipids. PMID:24078261

  4. 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

  5. NAA-modified DNA oligonucleotides with zwitterionic backbones: stereoselective synthesis of A-T phosphoramidite building blocks.

    PubMed

    Schmidtgall, Boris; Höbartner, Claudia; Ducho, Christian

    2015-01-01

    Modifications of the nucleic acid backbone are essential for the development of oligonucleotide-derived bioactive agents. The NAA-modification represents a novel artificial internucleotide linkage which enables the site-specific introduction of positive charges into the otherwise polyanionic backbone of DNA oligonucleotides. Following initial studies with the introduction of the NAA-linkage at T-T sites, it is now envisioned to prepare NAA-modified oligonucleotides bearing the modification at X-T motifs (X = A, C, G). We have therefore developed the efficient and stereoselective synthesis of NAA-linked 'dimeric' A-T phosphoramidite building blocks for automated DNA synthesis. Both the (S)- and the (R)-configured NAA-motifs were constructed with high diastereoselectivities to furnish two different phosphoramidite reagents, which were employed for the solid phase-supported automated synthesis of two NAA-modified DNA oligonucleotides. This represents a significant step to further establish the NAA-linkage as a useful addition to the existing 'toolbox' of backbone modifications for the design of bioactive oligonucleotide analogues.

  6. 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.

  7. 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

  8. 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

  9. 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.

  10. 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.

  11. Cerebral white matter blood flow and energy metabolism in multiple sclerosis.

    PubMed

    Steen, Christel; D'haeseleer, Miguel; Hoogduin, Johannes M; Fierens, Yves; Cambron, Melissa; Mostert, Jop P; Heersema, Dorothea J; Koch, Marcus W; De Keyser, Jacques

    2013-09-01

    Cerebral blood flow (CBF) is reduced in normal-appearing white matter (NAWM) of subjects with multiple sclerosis (MS), but the underlying mechanism is unknown. The objective of this article is to assess the relationship between reduced NAWM CBF and both axonal mitochondrial metabolism and astrocytic phosphocreatine (PCr) metabolism. Ten healthy controls and 25 MS subjects were studied with 3 Tesla magnetic resonance imaging. CBF was measured using pseudo-continuous arterial spin labeling. N-acetylaspartate/creatine (NAA/Cr) ratios (axonal mitochondrial metabolism) were obtained using (1)H-MR spectroscopy and PCr/β-ATP ratios using (31)P-MR spectroscopy. In centrum semiovale NAWM, we assessed correlations between CBF and both NAA/Cr and PCr/β-ATP ratios. Subjects with MS had a widespread reduction in CBF of NAWM (centrum semiovale, periventricular, frontal and occipital), and gray matter (frontoparietal cortex and thalamus). Compared to controls, NAA/Cr in NAWM of the centrum semiovale of MS subjects was decreased, whereas PCr/β-ATP was increased. We found no correlations between CBF and PCr/β-ATP. CBF and NAA/Cr correlated in controls (p = 0.02), but not in MS subjects (p = 0.68). Our results suggest that in MS patients there is no relationship between reduced CBF in NAWM and impaired axonal mitochondrial metabolism or astrocytic PCr metabolism.

  12. 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

  13. 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.

  14. 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.

  15. 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

  16. 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.

  17. 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

  18. 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

  19. 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.

  20. 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.

  1. Widespread extrahippocampal NAA/(Cr+Cho) abnormalities in TLE with and without mesial temporal sclerosis.

    PubMed

    Mueller, Susanne G; Ebel, Andreas; Barakos, Jerome; Scanlon, Cathy; Cheong, Ian; Finlay, Daniel; Garcia, Paul; Weiner, Michael W; Laxer, Kenneth D

    2011-04-01

    MR spectroscopy has demonstrated extrahippocampal NAA/(Cr+Cho) reductions in medial temporal lobe epilepsy with (TLE-MTS) and without (TLE-no) mesial temporal sclerosis. Because of the limited brain coverage of those previous studies, it was, however, not possible to assess differences in the distribution and extent of these abnormalities between TLE-MTS and TLE-no. This study used a 3D whole brain echoplanar spectroscopic imaging (EPSI) sequence to address the following questions: (1) Do TLE-MTS and TLE-no differ regarding severity and distribution of extrahippocampal NAA/(Cr+Cho) reductions? (2) Do extrahippocampal NAA/(Cr+Cho) reductions provide additional information for focus lateralization? Forty-three subjects (12 TLE-MTS, 13 TLE-no, 18 controls) were studied with 3D EPSI. Statistical parametric mapping (SPM2) was used to identify regions of significantly decreased NAA/(Cr+Cho) in TLE groups and in individual patients. TLE-MTS and TLE-no had widespread extrahippocampal NAA/(Cr+Cho) reductions. NAA/(Cr+Cho) reductions had a bilateral fronto-temporal distribution in TLE-MTS and a more diffuse, less well defined distribution in TLE-no. Extrahippocampal NAA/(Cr+Cho) decreases in the single subject analysis showed a large inter-individual variability and did not provide additional focus lateralizing information. Extrahippocampal NAA/(Cr+Cho) reductions in TLE-MTS and TLE-no are neither focal nor homogeneous. This reduces their value for focus lateralization and suggests a heterogeneous etiology of extrahippocampal spectroscopic metabolic abnormalities in TLE.

  2. 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.

  3. 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.

  4. 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.

  5. Magnetic resonance spectroscopy of current hand amputees reveals evidence for neuronal-level changes in former sensorimotor cortex

    PubMed Central

    Choi, In-Young; Lee, Phil; Peng, Huiling; Kaufman, Christina L.; Frey, Scott H.

    2017-01-01

    Deafferentation is accompanied by large-scale functional reorganization of maps in the primary sensory and motor areas of the hemisphere contralateral to injury. Animal models of deafferentation suggest a variety of cellular-level changes including depression of neuronal metabolism and even neuronal death. Whether similar neuronal changes contribute to patterns of reorganization within the contralateral sensorimotor cortex of chronic human amputees is uncertain. We used functional MRI-guided proton magnetic resonance spectroscopy to test the hypothesis that unilateral deafferentation is associated with lower levels of N-acetylaspartate (NAA, a putative marker of neuronal integrity) in the sensorimotor hand territory located contralateral to the missing hand in chronic amputees (n = 19) compared with the analogous hand territory of age- and sex-matched healthy controls (n = 28). We also tested whether former amputees [i.e., recipients of replanted (n = 3) or transplanted (n = 2) hands] exhibit NAA levels that are indistinguishable from controls, possible evidence for reversal of the effects of deafferentation. As predicted, relative to controls, current amputees exhibited lower levels of NAA that were negatively and significantly correlated with the time after amputation. Contrary to our prediction, NAA levels in both replanted and transplanted patients fell within the range of the current amputees. We suggest that lower levels of NAA in current amputees reflects altered neuronal integrity consequent to chronic deafferentation. Thus local changes in NAA levels may provide a means of assessing neuroplastic changes in deafferented cortex. Results from former amputees suggest that these changes may not be readily reversible through reafferentation. NEW & NOTEWORTHY This study is the first to use functional magnetic resonance-guided magnetic resonance spectroscopy to examine neurochemical mechanisms underlying functional reorganization in the primary somatosensory and

  6. 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

  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. 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.

  9. Effects of exogenous application of CPPU, NAA and GA4+7 on parthenocarpy and fruit quality in cucumber (Cucumis sativus L.).

    PubMed

    Qian, Chunlu; Ren, Nannan; Wang, Jingye; Xu, Qiang; Chen, Xuehao; Qi, Xiaohua

    2018-03-15

    In protected vegetable fields, plant growth regulators are often used to improve cucumber fruit growth. However, the effects of plant growth regulators on the appearance and nutritional quality of cucumber (Cucumis sativus L.) remain largely unknown. In the present study, 100 mg/L N-(2-chloro-4-pyridyl)-N'-phenylurea (CPPU), naphthaleneacetic acid (NAA) or gibberellin A4+A7 (GA 4+7 ) was applied to the female cucumber flowers 1 day before anthesis and at anthesis. The CPPU, NAA and GA 4+7 treatments resulted in parthenocarpic fruits with similar weights, sizes and shapes as the pollinated fruits. NAA treatment did not affect the appearance and nutritional characteristics of cucumber at harvest and after storage. CPPU treatment increased the flesh firmness at harvest but decreased phenolic acid and vitamin C contents after storage. GA 4+7 treatment decreased the flesh firmness but increased total flavonoids and protein content after storage. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. 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

  11. 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

  12. 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...

  13. 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...

  14. 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...

  15. 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...

  16. 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...

  17. Evaluation of treatment-induced cerebral white matter injury by using diffusion-tensor MR imaging: initial experience.

    PubMed

    Kitahara, Sawako; Nakasu, Satoshi; Murata, Kiyoshi; Sho, Keizen; Ito, Ryuta

    2005-10-01

    Treatment with chemotherapy and radiation therapy for brain tumors can cause white matter (WM) injury. Conventional MR imaging, however, cannot always depict treatment-induced transient WM abnormalities. We investigated the ability of diffusion-tensor (DT) MR imaging and proton MR spectroscopy to detect the treatment-induced transient changes within normal-appearing WM. DT MR imaging and proton MR spectroscopy were performed in 8 patients treated with a combination of surgery, chemotherapy, and radiation therapy for brain tumors (17 examinations) and 11 age-matched controls. Apparent diffusion coefficient (ADC) value, fractional anisotropy (FA) value, and N-acetylaspartate (NAA)/creatine (Cr) ratio were obtained from 27 hemispheres with normal-appearing WM in the patients. We divided the datasets of isotropic ADC, FA, and NAA/Cr, on the basis of the time period after completion of radiation therapy, into 4 groups: group 1 (0-2 months; n = 10), group 2 (3-5 months; n = 5), group 3 (6-9 months; n = 7), and group 4 (10-12 months; n = 5). We compared averages of mean isotropic ADC, mean FA, and NAA/Cr of each patient group with those of the control group by using a t test. In the group 2, averages of mean FA and NAA/Cr decreased and average of mean isotopic ADC increased in comparison with those of the control group (P = .004, .04, and .0085, respectively). There were no significant differences in the averages between the control group and patient groups 1, 3, and 4. DT MR imaging and proton MR spectroscopy can provide quantitative indices that may reflect treatment-induced transient derangement of normal-appearing WM.

  18. 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

  19. (1)H-magnetic resonance spectroscopy in social anxiety disorder.

    PubMed

    Howells, Fleur M; Hattingh, Coenraad J; Syal, Supriya; Breet, Elsie; Stein, Dan J; Lochner, Christine

    2015-04-03

    Social anxiety disorder (SAD) is characterized by excessive anxiety about social interaction or performance situations, leading to avoidance and clinically significant distress. A growing literature on the neurobiology of SAD has suggested that the reward/avoidance basal ganglia circuitry in general and the glutamatergic system in particular may play a role. In the current study, we investigated (1)H-magnetic resonance spectroscopy ((1)H-MRS) concentrations in cortical, striatal, and thalamic circuitry, as well as their associations with measures of social anxiety and related symptoms, in patients with primary SAD. Eighteen adult individuals with SAD and 19 age- and sex- matched controls participated in this study. (1)H-MRS was used to determine relative metabolite concentrations in the anterior cingulate cortex (ACC) using single voxel spectroscopy (reporting relative N-acetyl-aspartate (NAA), N-acetyl-aspartate with N-acetyl-aspartyl-glutamate (NAA+NAAG), glycerophosphocholine with phosphocholine (GPC+PCh), myo-inositol, glutamate (Glu), and glutamate with its precursor glutamine (Glu+Gln)), and the caudate, putamen and thalami bilaterally using two dimensional chemical shift imaging (reporting relative NAA+NAAG and GPC+PCh). Relationships between metabolite concentrations and measures of social anxiety and related symptoms were also determined. Measures of social anxiety included symptom severity, blushing propensity, and gaze anxiety/avoidance. We found, first, decreased relative glutamate concentration in the ACC of SAD and changes in myo-inositol with measures of social anxiety. Second, NAA metabolite concentration was increased in thalamus of SAD, and choline metabolite concentrations were related to measures of social anxiety. Lastly, choline metabolite concentration in the caudate and putamen showed changes in relation to measures of social anxiety. These findings are consistent with evidence that the reward/avoidance basal ganglia circuitry, as well as

  20. 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

  1. 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.

  2. Cerebral hemodynamics and metabolism in patients with symptomatic occlusion of the internal carotid artery.

    PubMed

    Rutgers, D R; van Osch, M J P; Kappelle, L J; Mali, W P T M; van der Grond, J

    2003-03-01

    The goals of this study were to investigate (1) whether the concentrations of choline, creatine, and N-acetyl aspartate (NAA) in cerebral white matter are changed in patients with symptomatic occlusion of the internal carotid artery (ICA) and (2) whether possible changes in metabolite concentration are related to regional cerebral perfusion or cerebral vasoreactivity. In 19 patients (mean+/-SD age, 60+/-9 years), white matter metabolite concentrations were measured with proton MR spectroscopic imaging on average 4+/-2 months after symptoms occurred. In selected voxels, corresponding cerebral blood flow and volume, mean transit time, and time-to-bolus peak were determined with dynamic susceptibility contrast MRI. Cerebral CO2 reactivity was determined with transcranial Doppler sonography. No significant changes in choline and creatine concentrations were observed. NAA concentration was significantly reduced in the hemisphere on the side of the symptomatic ICA (9.1+/-1.7 mmol/L) compared with the contralateral hemisphere (10.5+/-1.7 mmol/L, P<0.005) and control subjects (10.5+/-0.9 mmol/L, P<0.01). Although no significant interhemispheric difference in NAA concentration was found in patients who presented with retinal ischemia, patients with cerebral ischemia had a significantly lower NAA concentration in the symptomatic hemisphere (9.0+/-1.7 mmol/L) compared with the asymptomatic hemisphere (10.4+/-1.6 mmol/L, P<0.05). In all patients, NAA concentration was not significantly correlated with quantitative cerebral perfusion parameters or CO2 reactivity. Patients with symptomatic ICA occlusion may show chronic neuronal damage in cerebral white matter as evidenced by reduced NAA concentration. This seems to be related to previous symptomatology rather than to the cerebral hemodynamic status in a chronic stage.

  3. 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.

  4. 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.

  5. 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.

  6. 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

  7. Synthesis of zeolite NaA membrane from fused fly ash extract.

    PubMed

    Ameh, Alechine E; Musyoka, Nicholas M; Fatoba, Ojo O; Syrtsova, Daria A; Teplyakov, Vladimir V; Petrik, Leslie F

    2016-01-01

    Zeolite-NaA membranes were synthesized from an extract of fused South African fly ash on a porous titanium support by a secondary growth method. The influence of the synthesis molar regime on the formation of zeolite NaA membrane layer was investigated. Two synthesis mixtures were generated by adding either aluminium hydroxide or sodium aluminate to the fused fly ash extract. The feedstock material and the synthesized membranes were characterized by X-diffraction (XRD), scanning electron microscopy (SEM) and X-ray fluorescence spectroscopy (XRF). It was found by XRD and SEM that the cubic crystals of a typical zeolite NaA with a dense intergrown layer was formed on the porous Ti support. The study shows that the source of Al used had an effect on the membrane integrity as sodium aluminate provided the appropriate amount of Na(+) to form a coherent membrane of zeolite NaA, whereas aluminium hydroxide did not. Morphological, the single hydrothermal stage seeded support formed an interlocked array of zeolite NaA particles with neighbouring crystals. Also, a robust, continuous and well-intergrown zeolite NaA membrane was formed with neighbouring crystals of zeolite fused to each other after the multiple stage synthesis. The synthesized membrane was permeable to He (6.0 × 10(6) L m(-2)h(-1) atm(-1)) and CO2 (5.6 × 10(6) L m(-2)h(-1) atm(-1)), which indicate that the layer of the membrane was firmly attached to the porous Ti support. Membrane selectivity was maintained showing membrane integrity with permselectivity of 1.1, showing that a waste feedstock, fly ash, could be utilized for preparing robust zeolite NaA membranes on Ti support.

  8. 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.

  9. 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...

  10. 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

  11. 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.

  12. 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.

  13. 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.

  14. 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

  15. 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.

  16. 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

  17. 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

  18. Prefrontal NAA and Glx Levels in Different Stages of Psychotic Disorders: a 3T 1H-MRS Study.

    PubMed

    Liemburg, Edith; Sibeijn-Kuiper, Anita; Bais, Leonie; Pijnenborg, Gerdina; Knegtering, Henderikus; van der Velde, Jorien; Opmeer, Esther; de Vos, Annerieke; Dlabac-De Lange, Jozarni; Wunderink, Lex; Aleman, André

    2016-02-23

    H-Magnetic Resonance Spectroscopy ((1)H-MRS) can offer insights in various neuropathologies by measuring metabolite levels in the brain. In the current study we investigated the levels of glutamate + glutamine (Glx, neurotransmitter and precursor) and N-Acetyl Aspartate + glutamic acid (NAA + NAAG; neuronal viability) in the prefrontal cortex of patients with a psychotic disorder and people at Ultra High Risk (UHR) for psychosis. A (1)H-MRS spectrum was acquired in 31 patients with a recent onset psychotic disorder and 60 with a chronic state, 16 UHR patients and 36 healthy controls. Absolute metabolite levels were calculated using LCModel with a reference water peak. Groups were compared while taking into account age and partial volume effects. Moreover, we investigated associations with positive and negative symptoms, duration of illness, and antipsychotic treatment in patients. The most notable finding is that chronicity of schizophrenia was related to decreased levels of Glx and NAA. On the other hand, although on an exploratory note, UHR showed increased levels of prefrontal Glx and NAA levels with increasing age. Our results may indicate an initial Glx and NAA increase and subsequent decrease during illness progression that may be related to the neurotoxic effects of glutamate.

  19. 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.

  20. Association between memory impairment and brain metabolite concentrations in North Korean refugees with posttraumatic stress disorder.

    PubMed

    Shin, Jung Eun; Choi, Chi-Hoon; Lee, Jong Min; Kwon, Jun Soo; Lee, So Hee; Kim, Hyun-Chung; Han, Na Young; Choi, Soo-Hee; Yoo, So Young

    2017-01-01

    Individuals with posttraumatic stress disorder (PTSD) had experiences of enormous psychological stress that can result in neurocognitive and neurochemical changes. To date, the causal relationship between them remains unclear. The present study is to investigate the association between neurocognitive characteristics and neural metabolite concentrations in North Korean refugees with PTSD. A total of 53 North Korean refugees with or without PTSD underwent neurocognitive function tests. For neural metabolite scanning, magnetic resonance spectroscopy of the hippocampus and anterior cingulate cortex (ACC) has been conducted. We assessed between-group differences in neurocognitive test scores and metabolite levels. Additionally, a multiple regression analysis was carried out to evaluate the association between neurocognitive function and metabolite levels in patients with PTSD. Memory function, but not other neurocognitive functions, was significantly lower in the PTSD group compared with the non-PTSD group. Hippocampal N-acetylaspartate (NAA) levels were not different between groups; however, NAA levels were significantly lower in the ACC of the PTSD group than the non-PTSD group (t = 2.424, p = 0.019). The multiple regression analysis showed a negative association between hippocampal NAA levels and delayed recall score on the auditory verbal learning test (β = -1.744, p = 0.011) in the non-PTSD group, but not in the PTSD group. We identified specific memory impairment and the role of NAA levels in PTSD. Our findings suggest that hippocampal NAA has a protective role in memory impairment and development of PTSD after exposure to traumatic events.

  1. 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

  2. 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

  3. 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.

  4. In VivoLactate Editing with Simultaneous Detection of Choline, Creatine, NAA, and Lipid Singlets at 1.5 T Using PRESS Excitation with Applications to the Study of Brain and Head and Neck Tumors

    NASA Astrophysics Data System (ADS)

    Star-Lack, Josh; Spielman, Daniel; Adalsteinsson, Elfar; Kurhanewicz, John; Terris, David J.; Vigneron, Daniel B.

    1998-08-01

    Two T2-independentJ-difference lactate editing schemes for the PRESS magnetic resonance spectroscopy localization sequence are introduced. The techniques, which allow for simultaneous acquisition of the lactate doublet (1.3 ppm) and edited singlets upfield of and including choline (3.2 ppm), exploit the dependence of the in-phase intensity of the methyl doublet upon the time interval separating two inversion (BASING) pulses applied to its coupling partner after initial excitation. Editing method 1, which allows for echo times TE =n/J(n= 1, 2, 3, …), alters the BASING carrier frequency for each of two cycles so that, for one cycle, the quartet is inverted, whereas, for the other cycle, the quartet is unaffected. Method 2, which also provides water suppression, allows for editing for TE > 1/Jby alternating, between cycles, the time interval separating the inversion pulses. Experimental results were obtained at 1.5 T using a Shinnar Le-Roux-designed maximum phase inversion pulse with a filter transition bandwidth of 55 Hz. Spectra were acquired from phantoms andin vivofrom the human brain and neck. In a neck muscle study, the lipid suppression factor, achieved partly through the use of a novel phase regularization algorithm, was measured to be over 103. Spectra acquired from a primary brain and a metastatic neck tumor demonstrated the presence of lactate and choline signals consistent with abnormal spectral patterns. The advantages and limitations of the methods are analyzed theoretically and experimentally, and significance of the results is discussed.

  5. 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.

  6. Severity of experimental traumatic brain injury modulates changes in concentrations of cerebral free amino acids.

    PubMed

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

    2017-03-01

    In this study, concentrations of free amino acids (FAA) and amino group containing compounds (AGCC) following graded diffuse traumatic brain injury (mild TBI, mTBI; severe TBI, sTBI) were evaluated. After 6, 12, 24, 48 and 120 hr aspartate (Asp), glutamate (Glu), asparagine (Asn), serine (Ser), glutamine (Gln), histidine (His), glycine (Gly), threonine (Thr), citrulline (Cit), arginine (Arg), alanine (Ala), taurine (Tau), γ-aminobutyrate (GABA), tyrosine (Tyr), S-adenosylhomocysteine (SAH), l-cystathionine (l-Cystat), valine (Val), methionine (Met), tryptophane (Trp), phenylalanine (Phe), isoleucine (Ile), leucine (Leu), ornithine (Orn), lysine (Lys), plus N-acetylaspartate (NAA) were determined in whole brain extracts (n = 6 rats at each time for both TBI levels). Sham-operated animals (n = 6) were used as controls. Results demonstrated that mTBI caused modest, transient changes in NAA, Asp, GABA, Gly, Arg. Following sTBI, animals showed profound, long-lasting modifications of Glu, Gln, NAA, Asp, GABA, Ser, Gly, Ala, Arg, Citr, Tau, Met, SAH, l-Cystat, Tyr and Phe. Increase in Glu and Gln, depletion of NAA and Asp increase, suggested a link between NAA hydrolysis and excitotoxicity after sTBI. Additionally, sTBI rats showed net imbalances of the Glu-Gln/GABA cycle between neurons and astrocytes, and of the methyl-cycle (demonstrated by decrease in Met, and increase in SAH and l-Cystat), throughout the post-injury period. Besides evidencing new potential targets for novel pharmacological treatments, these results suggest that the force acting on the brain tissue at the time of the impact is the main determinant of the reactions ignited and involving amino acid metabolism. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  7. 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.

  8. 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.

  9. Chronic intermittent but not constant hypoxia decreases NAA/Cr ratios in neonatal mouse hippocampus and thalamus.

    PubMed

    Douglas, Robert M; Miyasaka, Naoyuki; Takahashi, Kan; Latuszek-Barrantes, Adrianna; Haddad, Gabriel G; Hetherington, Hoby P

    2007-03-01

    Chronic constant hypoxia (CCH) and chronic intermittent hypoxia (CIH) are known to have deleterious effects on the central nervous system. Because of the difference in the pattern of hypoxic exposure, it is possible that the pathological outcome would vary. The N-acetyl aspartate/creatine (NAA/Cr) ratio is a reliable marker of neuronal integrity, and this can be noninvasively measured by proton nuclear magnetic resonance spectroscopy. P2 CD1 mouse pups with their dams were exposed to either CCH, where the Fi(O(2)) was maintained at 11% continuously or to CIH, where the Fi(O(2)) was varied between 21 and 11% every 4 min. P30 mice exposed to intermittent hypoxia for 4 wk demonstrated a significant decrease in the NAA/Cr ratio in the hippocampus and thalamus, which was reversed by a subsequent exposure to 4 wk of normoxia. Meanwhile, mice exposed to 4 wk of constant hypoxia did not demonstrate any differences in their NAA/Cr ratios from controls in these brain regions. These results indicate that an intermittent pattern of hypoxic exposure may have a more adverse effect on neuronal function and integrity than a continuous one. The reversal of NAA/Cr levels to baseline during the return to normoxia indicates that therapeutic strategies targeted at alleviating the intermittent hypoxic stress in diseases, such as obstructive sleep apnea, have the potential for inducing significant neurocognitive recovery in these patients.

  10. Choline Supplementation Prevents a Hallmark Disturbance of Kwashiorkor in Weanling Mice Fed a Maize Vegetable Diet: Hepatic Steatosis of Undernutrition.

    PubMed

    May, Thaddaeus; Klatt, Kevin C; Smith, Jacob; Castro, Eumenia; Manary, Mark; Caudill, Marie A; Jahoor, Farook; Fiorotto, Marta L

    2018-05-22

    Hepatic steatosis is a hallmark feature of kwashiorkor malnutrition. However, the pathogenesis of hepatic steatosis in kwashiorkor is uncertain. Our objective was to develop a mouse model of childhood undernutrition in order to test the hypothesis that feeding a maize vegetable diet (MVD), like that consumed by children at risk for kwashiorkor, will cause hepatic steatosis which is prevented by supplementation with choline. A MVD was developed with locally sourced organic ingredients, and fed to weanling mice ( n = 9) for 6 or 13 days. An additional group of mice ( n = 4) were fed a choline supplemented MVD. Weight, body composition, and liver changes were compared to control mice ( n = 10) at the beginning and end of the study. The MVD resulted in reduced weight gain and hepatic steatosis. Choline supplementation prevented hepatic steatosis and was associated with increased hepatic concentrations of the methyl donor betaine. Our findings show that (1) feeding a MVD to weanling mice rapidly induces hepatic steatosis, which is a hallmark disturbance of kwashiorkor; and that (2) hepatic steatosis associated with feeding a MVD is prevented by choline supplementation. These findings support the concept that insufficient choline intake may contribute to the pathogenesis of hepatic steatosis in kwashiorkor.

  11. Choline Supplementation Prevents a Hallmark Disturbance of Kwashiorkor in Weanling Mice Fed a Maize Vegetable Diet: Hepatic Steatosis of Undernutrition

    PubMed Central

    May, Thaddaeus; Klatt, Kevin C.; Smith, Jacob; Castro, Eumenia; Manary, Mark; Caudill, Marie A.; Jahoor, Farook

    2018-01-01

    Hepatic steatosis is a hallmark feature of kwashiorkor malnutrition. However, the pathogenesis of hepatic steatosis in kwashiorkor is uncertain. Our objective was to develop a mouse model of childhood undernutrition in order to test the hypothesis that feeding a maize vegetable diet (MVD), like that consumed by children at risk for kwashiorkor, will cause hepatic steatosis which is prevented by supplementation with choline. A MVD was developed with locally sourced organic ingredients, and fed to weanling mice (n = 9) for 6 or 13 days. An additional group of mice (n = 4) were fed a choline supplemented MVD. Weight, body composition, and liver changes were compared to control mice (n = 10) at the beginning and end of the study. The MVD resulted in reduced weight gain and hepatic steatosis. Choline supplementation prevented hepatic steatosis and was associated with increased hepatic concentrations of the methyl donor betaine. Our findings show that (1) feeding a MVD to weanling mice rapidly induces hepatic steatosis, which is a hallmark disturbance of kwashiorkor; and that (2) hepatic steatosis associated with feeding a MVD is prevented by choline supplementation. These findings support the concept that insufficient choline intake may contribute to the pathogenesis of hepatic steatosis in kwashiorkor. PMID:29786674

  12. 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.

  13. Choline deficiency impairs intestinal lipid metabolism in the lactating rat.

    PubMed

    da Silva, Robin P; Kelly, Karen B; Lewis, Erin D; Leonard, Kelly-Ann; Goruk, Sue; Curtis, Jonathan M; Vine, Donna F; Proctor, Spencer D; Field, Catherine J; Jacobs, René L

    2015-10-01

    Choline is a precursor to phosphatidylcholine (PC), a structural molecule in cellular membranes that is crucial for cell growth and function. PC is also required for the secretion of lipoprotein particles from liver and intestine. Choline requirements are increased during lactation when maternal choline is supplied to the offspring through breast milk. To investigate the effect of dietary choline on intestinal lipid metabolism during lactation, choline-supplemented (CS), phosphatidylcholine-supplemented (PCS) or choline-deficient (CD) diets were fed to dams during the suckling period. CD dams had lower plasma triacylglycerol, cholesterol and apoB in the fasted state and following a fat-challenge (P < .05). There was a higher content of neutral lipids and lower content of PC in the intestine of CD dams, compared with CS and PCS fed animals (P < .05). In addition, there was lower (P < .05) villus height in CD dams, which indicated a reduced absorptive surface area in the intestine. Choline is critical for the absorption of fat in lactating rats and choline deficiency alters intestinal morphology and impairs chylomicron secretion by limiting the supply of PC. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. Structure and biological function of ENPP6, a choline-specific glycerophosphodiester-phosphodiesterase

    PubMed Central

    Morita, Junko; Kano, Kuniyuki; Kato, Kazuki; Takita, Hiroyuki; Sakagami, Hideki; Yamamoto, Yasuo; Mihara, Emiko; Ueda, Hirofumi; Sato, Takanao; Tokuyama, Hidetoshi; Arai, Hiroyuki; Asou, Hiroaki; Takagi, Junichi; Ishitani, Ryuichiro; Nishimasu, Hiroshi; Nureki, Osamu; Aoki, Junken

    2016-01-01

    Choline is an essential nutrient for all living cells and is produced extracellularly by sequential degradation of phosphatidylcholine (PC). However, little is known about how choline is produced extracellularly. Here, we report that ENPP6, a choline-specific phosphodiesterase, hydrolyzes glycerophosphocholine (GPC), a degradation product of PC, as a physiological substrate and participates in choline metabolism. ENPP6 is highly expressed in liver sinusoidal endothelial cells and developing oligodendrocytes, which actively incorporate choline and synthesize PC. ENPP6-deficient mice exhibited fatty liver and hypomyelination, well known choline-deficient phenotypes. The choline moiety of GPC was incorporated into PC in an ENPP6-dependent manner both in vivo and in vitro. The crystal structure of ENPP6 in complex with phosphocholine revealed that the choline moiety of the phosphocholine is recognized by a choline-binding pocket formed by conserved aromatic and acidic residues. The present study provides the molecular basis for ENPP6-mediated choline metabolism at atomic, cellular and tissue levels. PMID:26888014

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

    PubMed Central

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

    2017-01-01

    Background 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 odds ratio (OR) 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 development 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, P=0.71 and P=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 risks across all anatomical subsites, suggesting a role of altered choline metabolism in colorectal cancer pathogenesis. PMID:28077427

  16. Novel choline esterase based sensor for monitoring of organophosphorus pollutants

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

    Wilkins, E.S.; Ghindilis, A.L.; Atanasov, P.

    1996-12-31

    Organophosphorus compounds are significant major environmental pollutants due to their intensive use as pesticides. The modern techniques based on inhibition of choline esterase enzyme activity are discussed. Potentiometric electrodes based on detection of choline esterase inhibition by analytes has been developed. The detection of choline esterase activity is based on the novel principle of molecular transduction. Immobilized peroxidase acting as the molecular transducer, catalyzes the electroreduction of hydrogen peroxide by direct (mediatorless) electron transfer. The sensing element consists of a carbon based electrode containing an assembly of co-immobilized enzymes: choline esterase, choline oxidase and peroxidase.

  17. Feeding a Mixture of Choline Forms to Lactating Dams Improves the Development of the Immune System in Sprague-Dawley Rat Offspring.

    PubMed

    Richard, Caroline; Lewis, Erin D; Goruk, Susan; Wadge, Emily; Curtis, Jonathan M; Jacobs, René L; Field, Catherine J

    2017-06-02

    Dietary choline is essential during lactation, but few studies have examined the implications of feeding a mixture of choline forms on immune function. This study investigates the impact of feeding lactating dams different mixtures of choline forms, similar to those in human diets, on the development and later immune function of suckled offspring. Sprague-Dawley lactating dams ( n = 6/diet) were randomized to consume one of three diets, containing 1 g/kg choline: Control (100% free choline (FC)), Mixed Choline (MC: 50% phosphatidylcholine (PC), 25% FC, 25% glycerophosphocholine (GPC)), or High GPC (HGPC: 75% GPC, 12.5% PC, 12.5% FC). At weaning, female pups ( n = 2/dam) were fed the Control diet until 10 weeks. At 3 weeks, MC and HGPC pups were heavier and their splenocytes had a higher proportion of helper T cells expressing CD25 and CD28 and produced less interferon gamma (IFN-γ) and tumor-necrosis factor-α (TNF-α) after Concanavalin A stimulation vs. Control pups ( p < 0.05). At 10 weeks, MC and HGPC offspring had a lower proportion of macrophages and dendritic cells and produced less interleukin (IL)-1β but more IL-10 after lipopolysaccharide stimulation vs. Control pups ( p < 0.05). In summary, feeding mixed choline diets during lactation improved T cell phenotype/function at the end of suckling and programmed a less inflammatory response later in life.

  18. Feeding a Mixture of Choline Forms to Lactating Dams Improves the Development of the Immune System in Sprague-Dawley Rat Offspring

    PubMed Central

    Richard, Caroline; Lewis, Erin D.; Goruk, Susan; Wadge, Emily; Curtis, Jonathan M.; Jacobs, René L.; Field, Catherine J.

    2017-01-01

    Dietary choline is essential during lactation, but few studies have examined the implications of feeding a mixture of choline forms on immune function. This study investigates the impact of feeding lactating dams different mixtures of choline forms, similar to those in human diets, on the development and later immune function of suckled offspring. Sprague-Dawley lactating dams (n = 6/diet) were randomized to consume one of three diets, containing 1 g/kg choline: Control (100% free choline (FC)), Mixed Choline (MC: 50% phosphatidylcholine (PC), 25% FC, 25% glycerophosphocholine (GPC)), or High GPC (HGPC: 75% GPC, 12.5% PC, 12.5% FC). At weaning, female pups (n = 2/dam) were fed the Control diet until 10 weeks. At 3 weeks, MC and HGPC pups were heavier and their splenocytes had a higher proportion of helper T cells expressing CD25 and CD28 and produced less interferon gamma (IFN-γ) and tumor-necrosis factor-α (TNF-α) after Concanavalin A stimulation vs. Control pups (p < 0.05). At 10 weeks, MC and HGPC offspring had a lower proportion of macrophages and dendritic cells and produced less interleukin (IL)-1β but more IL-10 after lipopolysaccharide stimulation vs. Control pups (p < 0.05). In summary, feeding mixed choline diets during lactation improved T cell phenotype/function at the end of suckling and programmed a less inflammatory response later in life. PMID:28574475

  19. Substrate Binding and Catalytic Mechanism of Human Choline Acetyltransferase

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

    Kim,A.; Rylett, J.; Shilton, B.

    2006-01-01

    Choline acetyltransferase (ChAT) catalyzes the synthesis of the neurotransmitter acetylcholine from choline and acetyl-CoA, and its presence is a defining feature of cholinergic neurons. We report the structure of human ChAT to a resolution of 2.2 {angstrom} along with structures for binary complexes of ChAT with choline, CoA, and a nonhydrolyzable acetyl-CoA analogue, S-(2-oxopropyl)-CoA. The ChAT-choline complex shows which features of choline are important for binding and explains how modifications of the choline trimethylammonium group can be tolerated by the enzyme. A detailed model of the ternary Michaelis complex fully supports the direct transfer of the acetyl group from acetyl-CoAmore » to choline through a mechanism similar to that seen in the serine hydrolases for the formation of an acyl-enzyme intermediate. Domain movements accompany CoA binding, and a surface loop, which is disordered in the unliganded enzyme, becomes localized and binds directly to the phosphates of CoA, stabilizing the complex. Interactions between this surface loop and CoA may function to lower the K{sub M} for CoA and could be important for phosphorylation-dependent regulation of ChAT activity.« less

  20. Deletion of murine choline dehydrogenase results in diminished sperm motility

    PubMed Central

    Johnson, Amy R.; Craciunescu, Corneliu N.; Guo, Zhong; Teng, Ya-Wen; Thresher, Randy J.; Blusztajn, Jan K.; Zeisel, Steven H.

    2010-01-01

    Choline dehydrogenase (CHDH) catalyzes the conversion of choline to betaine, an important methyl donor and organic osmolyte. We have previously identified single nucleotide polymorphisms (SNPs) in the human CHDH gene that, when present, seem to alter the activity of the CHDH enzyme. These SNPs occur frequently in humans. We created a Chdh−/− mouse to determine the functional effects of mutations that result in decreased CHDH activity. Chdh deletion did not affect fetal viability or alter growth or survival of these mice. Only one of eleven Chdh−/− males was able to reproduce. Loss of CHDH activity resulted in decreased testicular betaine and increased choline and PCho concentrations. Chdh+/+ and Chdh−/− mice produced comparable amounts of sperm; the impaired fertility was due to diminished sperm motility in the Chdh−/− males. Transmission electron microscopy revealed abnormal mitochondrial morphology in Chdh−/− sperm. ATP content, total mitochondrial dehydrogenase activity and inner mitochondrial membrane polarization were all significantly reduced in sperm from Chdh−/− animals. Mitochondrial changes were also detected in liver, kidney, heart, and testis tissues. We suggest that men who have SNPs in CHDH that decrease the activity of the CHDH enzyme could have decreased sperm motility and fertility.—Johnson, A. R., Craciunescu, C. N., Guo, Z., Teng, Y.-W., Thresher, R. J., Blusztajn, J. K., Zeisel, S. H. Deletion of murine choline dehydrogenase results in diminished sperm motility. PMID:20371614