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Dietary glutamic acid and aspartic acid as biomarkers for predicting diabetic retinopathy.
Park, SY, Kim, J, Son, JI, Rhee, SY, Kim, DY, Chon, S, Lim, H, Woo, JT
Scientific reports. 2021;(1):7244
Abstract
The screening rate of diabetic retinopathy (DR) is low despite the importance of early diagnosis. We investigated the predictive value of dietary glutamic acid and aspartic acid for diagnosis of DR using the Korea National Diabetes Program cohort study. The 2067 patients with type 2 diabetes without DR were included. The baseline intakes of energy, glutamic acid and aspartic acid were assessed using a 3-day food records. The risk of DR incidence based on intake of glutamic acid and aspartic acid was analyzed. The DR group was older, and had higher HbA1c, longer DM duration, lower education level and income than non-DR group (all p < 0.05). The intake of total energy, glutamic acid and aspartic acid were lower in DR group than non-DR group (p = 0.010, p = 0.025 and p = 0.042, respectively). There was no difference in the risk of developing DR according to the intake of glutamic acid and ascorbic acid. But, aspartic acid intake had a negative correlation with PDR. Hence, the intake of glutamic acid and aspartic acid did not affect in DR incidence. However, lower aspartic acid intake affected the PDR incidence.
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Effects of acute N-acetylcysteine challenge on cortical glutathione and glutamate in schizophrenia: A pilot in vivo proton magnetic resonance spectroscopy study.
Girgis, RR, Baker, S, Mao, X, Gil, R, Javitt, DC, Kantrowitz, JT, Gu, M, Spielman, DM, Ojeil, N, Xu, X, et al
Psychiatry research. 2019;:78-85
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Abstract
Findings from in vivo brain proton magnetic resonance spectroscopy (1H MRS) and preclinical studies have suggested region- and medication status-dependent increases in glutamate (Glu) levels and deficiencies in glutathione (GSH) levels in schizophrenia. N-acetylcysteine (NAC), a GSH synthesis precursor, has demonstrated modest clinical benefit in schizophrenia. The objective of this study was to examine the effects of acute administration of NAC on GSH and Glu levels measured with 1H MRS in 19 patients with schizophrenia and 20 healthy control subjects. Levels of GSH were acquired in dorsal anterior cingulate cortex (dACC), and those of Glu in dACC and medial prefrontal cortex (mPFC), at baseline and 60 min following acute oral administration of 2400 mg of NAC. No differences in the levels of GSH or Glu were found at baseline or following NAC administration between patients with schizophrenia and control subjects in either of the targeted brain regions. Future studies measuring GSH levels in brain regions previously found to exhibit glutamatergic abnormalities or using genetic polymorphisms, while controlling for the age and medication status of the cohorts, are warranted to better identify groups of patients more likely to respond to NAC and its mode of action and mechanisms.
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Clofibrate inhibits the umami-savory taste of glutamate.
Kochem, M, Breslin, PA
PloS one. 2017;(3):e0172534
Abstract
In humans, umami taste can increase the palatability of foods rich in the amino acids glutamate and aspartate and the 5'-ribonucleotides IMP and GMP. Umami taste is transduced, in part, by T1R1-T1R3, a heteromeric G-protein coupled receptor. Umami perception is inhibited by sodium lactisole, which binds to the T1R3 subunit in vitro. Lactisole is structurally similar to the fibrate drugs. Clofibric acid, a lipid lowering drug, also binds the T1R3 subunit in vitro. The purpose of this study was to determine whether clofibric acid inhibits the umami taste of glutamate in human subjects. Ten participants rated the umami taste intensity elicited by 20 mM monosodium glutamate (MSG) mixed with varying concentrations of clofibric acid (0 to 16 mM). In addition, fourteen participants rated the effect of 1.4 mM clofibric acid on umami enhancement by 5' ribonucleotides. Participants were instructed to rate perceived intensity using a general Labeled Magnitude Scale (gLMS). Each participant was tested in triplicate. Clofibric acid inhibited umami taste intensity from 20 mM MSG in a dose dependent manner. Whereas MSG neat elicited "moderate" umami taste intensity, the addition of 16 mM clofibric acid elicited only "weak" umami intensity on average, and in some subjects no umami taste was elicited. We further show that 1.4 mM clofibric acid suppressed umami enhancement from GMP, but not from IMP. This study provides in vivo evidence that clofibric acid inhibits glutamate taste perception, presumably via T1R1-T1R3 inhibition, and lends further evidence that the T1R1-T1R3 receptor is the principal umami receptor in humans. T1R receptors are expressed extra-orally throughout the alimentary tract and in regulatory organs and are known to influence glucose and lipid metabolism. Whether clofibric acid as a lipid-lowering drug affects human metabolism, in part, through T1R inhibition warrants further examination.
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1H-magnetic resonance spectroscopy study of glutamate-related abnormality in bipolar disorder.
Kubo, H, Nakataki, M, Sumitani, S, Iga, JI, Numata, S, Kameoka, N, Watanabe, SY, Umehara, H, Kinoshita, M, Inoshita, M, et al
Journal of affective disorders. 2017;:139-144
Abstract
BACKGROUND Previous studies of patients with bipolar disorder (BD) using magnetic resonance spectroscopy (MRS) have shown neurophysiological abnormalities related to the glutamate (Glu)-glutamine (Gln) cycle, membrane turnover, and neuronal integrity, although the results were neither consistent nor conclusive. Recently it has been reported the Gln/Glu ratio is the most useful index, quantifying neuronal-glial interactions and the balance of glutamatergic metabolites In this MRS study, we elucidated the abnormalities of metabolites in a larger sample of patients with BD with a high-field MRI system. METHODS Sixty-two subjects (31 patients with BD and 31 healthy controls [HC]) underwent 3T proton MRS (1H-MRS) of the anterior cingulate cortex (ACC) and left basal ganglia (ltBG) using a stimulated echo acquisition mode (STEAM) sequence. RESULTS After verifying the data quality, 20 patients with BD and 23 age- and gender-matched HCs were compared using repeated-measures analysis of covariance (ANCOVA). Compared to the HC group, the BD group showed increased levels of Gln, creatine (Cr), N-acetyl aspartate (NAA), choline (Cho), and an increased ratio of Gln to Glu in the ACC, and increased Gln and Cho in the ltBG. These findings remained after the participants with BD were limited to only euthymic patients. After removing the influence of lithium (Li) and sodium valproate (VPA), we observed activated glutamatergic neurotransmission in the ACC but not in the ltBG. LIMITATIONS The present findings are cross-sectional and metabolites were measured in only two regions. CONCLUSIONS Our results support a wide range of metabolite changes in patients with BD involved in glutamatergic neurotransmission, membrane turnover, and neuronal integrity. Moreover, the elevation of Gln/Glu ratio suggested that hyperactivity of glutamatergic neurotransmission in the ACC is a disease marker for BD.
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Utility of [18F]FSPG PET to Image Hepatocellular Carcinoma: First Clinical Evaluation in a US Population.
Kavanaugh, G, Williams, J, Morris, AS, Nickels, ML, Walker, R, Koglin, N, Stephens, AW, Washington, MK, Geevarghese, SK, Liu, Q, et al
Molecular imaging and biology. 2016;(6):924-934
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PURPOSE Non-invasive imaging is central to hepatocellular carcinoma (HCC) diagnosis; however, conventional modalities are limited by smaller tumors and other chronic diseases that are often present in patients with HCC, such as cirrhosis. This pilot study evaluated the feasibility of (4S)-4-(3-[18F]fluoropropyl)-L-glutamic acid ([18F]FSPG) positron emission tomography (PET)/X-ray computed tomography (CT) to image HCC. [18F]FSPG PET/CT was compared to standard-of-care (SOC) magnetic resonance imaging (MRI) and CT, and [11C]acetate PET/CT, commonly used in this setting. We report the largest cohort of HCC patients imaged to date with [18F]FSPG PET/CT and present the first comparison to [11C]acetate PET/CT and SOC imaging. This study represents the first in a US HCC population, which is distinguished by different underlying comorbidities than non-US populations. PROCEDURES xC- transporter RNA and protein levels were evaluated in HCC and matched liver samples from The Cancer Genome Atlas (n = 16) and a tissue microarray (n = 83). Eleven HCC patients who underwent prior MRI or CT scans were imaged by [18F]FSPG PET/CT, with seven patients also imaged with [11C]acetate PET/CT. RESULTS xC- transporter RNA and protein levels were elevated in HCC samples compared to background liver. Over 50 % of low-grade HCCs and ~70 % of high-grade tumors exceeded background liver protein expression. [18F]FSPG PET/CT demonstrated a detection rate of 75 %. [18F]FSPG PET/CT also identified an HCC devoid of typical MRI enhancement pattern. Patients scanned with [18F]FSPG and [11C]acetate PET/CT exhibited a 90 and 70 % detection rate, respectively. In dually positive tumors, [18F]FSPG accumulation consistently resulted in significantly greater tumor-to-liver background ratios compared with [11C]acetate PET/CT. CONCLUSIONS [18F]FSPG PET/CT is a promising modality for HCC imaging, and larger studies are warranted to examine [18F]FSPG PET/CT impact on diagnosis and management of HCC. [18F]FSPG PET/CT may also be useful for phenotyping HCC tumor metabolism as part of precision cancer medicine.
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Effect of L-theanine on glutamatergic function in patients with schizophrenia.
Ota, M, Wakabayashi, C, Sato, N, Hori, H, Hattori, K, Teraishi, T, Ozawa, H, Okubo, T, Kunugi, H
Acta neuropsychiatrica. 2015;(5):291-6
Abstract
OBJECTIVES Glutamatergic dysfunction in the brain has been implicated in the pathophysiology of schizophrenia. Previous studies suggested that L-theanine affects the glutamatergic neurotransmission and ameliorates symptoms in patients with schizophrenia. The aims of the present study were twofold: to examine the possible effects of L-theanine on symptoms in chronic schizophrenia patients and to evaluate the changes in chemical mediators, including glutamate + glutamine (Glx), in the brain by using 1H magnetic resonance spectroscopy (MRS). METHOD The subjects were 17 patients with schizophrenia and 22 age- and sex-matched healthy subjects. L-theanine (250 mg/day) was added to the patients' ongoing antipsychotic treatment for 8 weeks. The outcome measures were the Positive and Negative Syndrome Scale (PANSS), Pittsburgh Sleep Quality Index scores and MRS results. RESULTS There were significant improvements in the PANSS positive scale and sleep quality after the L-theanine treatment. As for MRS, we found no significant differences in Glx levels before and after the 8 week L-theanine treatment. However, significant correlations were observed between baseline density of Glx and change in Glx density by l-theanine. CONCLUSIONS Our results suggest that L-theanine is effective in ameliorating positive symptoms and sleep quality in schizophrenia. The MRS findings suggest that L-theanine stabilises the glutamatergic concentration in the brain, which is a possible mechanism underlying the therapeutic effect.
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Brain magnetic resonance spectroscopy in episodic hepatic encephalopathy.
Chavarria, L, Alonso, J, García-Martínez, R, Simón-Talero, M, Ventura-Cots, M, Ramírez, C, Torrens, M, Vargas, V, Rovira, A, Córdoba, J
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2013;(2):272-7
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Brain magnetic resonance (MR) study has shown metabolic abnormalities and changes in water distribution of the brain tissue that may relate to the pathogenesis of hepatic encephalopathy (HE). We designed a study to investigate the disturbances in brain water and metabolites during episodic HE using a 3-T MR scanner. Cirrhotic patients with different grades of HE underwent MR during hospitalization (n=18). The MR was repeated at 6 weeks' follow-up (n=14). The results were compared with those of a group of healthy volunteers (n=8). During episodic HE, brain diffusion-weighted imaging showed a high apparent diffusion coefficient (ADC) (12% to 14%) that decreased during follow-up (-1% to -4%). These disturbances were accompanied by high glutamine (581%), low choline (-31%), and low myo-inositol (-86%) peaks on MR spectroscopy. In overt HE, patients showed high glutamine that decreased during follow-up (-22%). In addition, these patients exhibited a rise in plasma S100 beta and enlargement of brain white-matter lesions. In conclusion, several disturbances detected by MR support the presence of impaired brain water homeostasis during episodic HE. Although astrocytes have a major role in this condition, brain edema during episodic HE may be extracellular and does not appear to be directly responsible for the development of neurologic manifestations.
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Glutamine/glutamate metabolism studied with magnetic resonance spectroscopic imaging for the characterization of adrenal nodules and masses.
Goldman, SM, Nunes, TF, Melo, HJ, Dalavia, C, Szejnfeld, D, Kater, C, Andreoni, C, Szejnfeld, J, Ajzen, SA
BioMed research international. 2013;:835385
Abstract
PURPOSE To assess glutamine/glutamate (Glx) and lactate (Lac) metabolism using proton magnetic resonance spectroscopic imaging (1H-MRS) in order to differentiate between adrenal gland nodules and masses (adenomas, pheochromocytomas, carcinomas, and metastases). MATERIALS AND METHODS Institutional review board approval and informed consent were obtained. A total of 130 patients (47 men) with 132 adrenal nodules/masses were prospectively assessed (54 ± 14.8 years). A multivoxel system was used with a two-dimensional point-resolved spectroscopy/chemical-shift imaging sequence. Spectroscopic data were interpreted by visual inspection and peak amplitudes of lipids (Lip), choline (Cho), creatine (Cr), Lac, and Glx. Lac/Cr and Glx/Cr were calculated. Glx/Cr was assessed in relation to lesion size. RESULTS Statistically significant differences were observed in Glx/Cr results between adenomas and pheochromocytomas (P < 0.05), however, with a low positive predictive value (PPV). Glx levels were directly proportional to lesion size in carcinomas. A cutoff point of 1.44 was established for the differentiation between carcinomas larger versus smaller than 4 cm, with 75% sensitivity, 100% specificity, 100% PPV, and 80% accuracy. Lac/Cr results showed no differences across lesions. A cutoff point of -6.5 for Lac/Cr was established for carcinoma diagnosis. CONCLUSION Glx levels are directly proportional to lesion size in carcinomas. A cutoff point of -6.5 Lac/Cr differentiates carcinomas from noncarcinomas.
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Acute shift in glutamate concentrations following experimentally induced panic with cholecystokinin tetrapeptide--a 3T-MRS study in healthy subjects.
Zwanzger, P, Zavorotnyy, M, Gencheva, E, Diemer, J, Kugel, H, Heindel, W, Ruland, T, Ohrmann, P, Arolt, V, Domschke, K, et al
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2013;(9):1648-54
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According to preclinical studies, glutamate has been implicated in the pathogenesis of anxiety. In order to elucidate the role of glutamate in anxiety and panic in humans, brain glutamate+glutamine (Glx) levels were measured during cholecystokinin-tetrapeptide (CCK-4)-induced panic using magnetic resonance spectroscopy (MRS). Eighteen healthy subjects underwent a CCK-4 challenge. MR spectra were obtained from the anterior cingulate cortex (ACC) using a single voxel point-resolved spectroscopy method and analyzed using LCModel. A combined fitting of Glx was performed. Panic was assessed using the Acute Panic Inventory (API) and Panic Symptom Scale (PSS) scores. Moreover, hypothalamic-pituitary-adrenal axis stimulation was monitored throughout the challenge. There was a significant panic response following CCK-4 as revealed by a marked increase in both the panic scores (API: F(1,17)=149.41; p<0.0001; PSS: F(1,17)=88.03; p<0.0001) and heart rate (HR: F(1,17)=72.79; p<0.0001). MRS measures showed a significant increase of brain Glx/creatine (Glx/Cr) levels peaking at 2-10 min after challenge (F(1,17)=15.94; p=0.001). There was also a significant increase in CCK-4-related cortisol release (F(6,11)=8.68; p=0.002). Finally, significant positive correlations were found between baseline Glx/Cr and both APImax (r=0.598; p=0.009) and maximum heart rate (HR(max)) during challenge (r=0.519; p=0.027). Our results suggest that CCK-4-induced panic is accompanied by a significant glutamate increase in the bilateral ACC. The results add to the hypothesis of a disturbance of the inhibitory-excitatory equilibrium and suggest that apart from static alterations rapid and dynamic neurochemical changes might also be relevant for the neural control of panic attacks.
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Elevated glutamatergic compounds in pregenual anterior cingulate in pediatric autism spectrum disorder demonstrated by 1H MRS and 1H MRSI.
Bejjani, A, O'Neill, J, Kim, JA, Frew, AJ, Yee, VW, Ly, R, Kitchen, C, Salamon, N, McCracken, JT, Toga, AW, et al
PloS one. 2012;(7):e38786
Abstract
Recent research in autism spectrum disorder (ASD) has aroused interest in anterior cingulate cortex and in the neurometabolite glutamate. We report two studies of pregenual anterior cingulate cortex (pACC) in pediatric ASD. First, we acquired in vivo single-voxel proton magnetic resonance spectroscopy ((1)H MRS) in 8 children with ASD and 10 typically developing controls who were well matched for age, but with fewer males and higher IQ. In the ASD group in midline pACC, we found mean 17.7% elevation of glutamate + glutamine (Glx) (p<0.05) and 21.2% (p<0.001) decrement in creatine + phosphocreatine (Cr). We then performed a larger (26 subjects with ASD, 16 controls) follow-up study in samples now matched for age, gender, and IQ using proton magnetic resonance spectroscopic imaging ((1)H MRSI). Higher spatial resolution enabled bilateral pACC acquisition. Significant effects were restricted to right pACC where Glx (9.5%, p<0.05), Cr (6.7%, p<0.05), and N-acetyl-aspartate + N-acetyl-aspartyl-glutamate (10.2%, p<0.01) in the ASD sample were elevated above control. These two independent studies suggest hyperglutamatergia and other neurometabolic abnormalities in pACC in ASD, with possible right-lateralization. The hyperglutamatergic state may reflect an imbalance of excitation over inhibition in the brain as proposed in recent neurodevelopmental models of ASD.