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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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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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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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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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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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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.
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Brain biochemical effects of methylphenidate treatment using proton magnetic spectroscopy in youth with attention-deficit hyperactivity disorder: a controlled pilot study.
Hammerness, P, Biederman, J, Petty, C, Henin, A, Moore, CM
CNS neuroscience & therapeutics. 2012;(1):34-40
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INTRODUCTION This study conducted spectroscopic analyses using proton (1H) Magnetic Resonance Spectroscopy (at 4 Tesla) in a sample of adolescents with Attention Deficit Hyperactivity Disorder (ADHD), before and after treatment with extended release methylphenidate (OROS MPH), as compared to a sample of healthy comparators. AIMS The main aim of this study is to use 1H MRS to measure differences in brain biochemistry between adolescents with and without ADHD, and to assess changes in cerebral biochemistry, before and after stimulant treatment in ADHD youth. RESULTS Subjects with ADHD were medically healthy adolescents treated in an open label fashion with OROS MPH (mean dose: 54 mg/day; 0.90 mg/kg/day). Subjects with ADHD were scanned before and after OROS MPH treatment. Healthy comparators were scanned once. Magnetic resonance (MR) spectroscopy studies were performed on a 4.0 T Varian Unity/Inova MR scanner; proton spectra were acquired from the Anterior Cingulate Cortex (ACC). Data were analyzed using MANOVA and repeated measurement ANOVA. Higher metabolite ratios (Glutamate/myo-inositol, Glutamine/myo-inositol, Glutamate + Glutamine/myo-inositol) were observed in the ACC in untreated ADHD subjects as compared to controls, and to treated ADHD youth; these group differences did not reach the a priori threshold for statistical significance. CONCLUSIONS These preliminary findings suggest the presence of glutamatergic abnormalities in adolescents with ADHD, which may normalize with MPH treatment. Larger sample, controlled studies are needed to confirm these preliminary findings.
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Increased detectability of alpha brain glutamate/glutamine in neonatal hypoxic-ischemic encephalopathy.
Pu, Y, Li, QF, Zeng, CM, Gao, J, Qi, J, Luo, DX, Mahankali, S, Fox, PT, Gao, JH
AJNR. American journal of neuroradiology. 2000;(1):203-12
Abstract
BACKGROUND AND PURPOSE Proton MR spectroscopy (MRS) detectability of brain glutamate/glutamine (Glx) is increased in hypoxic-ischemic insults and is implicated in the neuronal injury and death that follows. Our aim was to correlate the proton MRS detectability of alpha-CH protons of Glx (alpha-Glx) with the Sarnat stage of neonatal hypoxic-ischemic encephalopathy (HIE). METHODS Initial and follow-up proton MRS studies at 1.9 T were performed in 28 neonates aged 1 to 7 days (seven healthy control subjects and 21 with HIE: 10 mild, nine moderate, and two severe) and in 12 neonates aged 13 to 17 days (12 with HIE: eight mild, three moderate, and one severe), respectively. Both point-resolved spectroscopy (PRESS) and stimulated-echo acquisition mode (STEAM) sequences were used. The spectral volume of interest was in the basal ganglia, thalami, and adjoining regions. The detectability of alpha-Glx was assessed by two different parameters: the detection rate of the alpha-Glx peak and the peak-area ratio of alpha-Glx to creatine and phosphocreatine. RESULTS On both the initial and follow-up PRESS studies, all the neonates with moderate and severe HIE showed an alpha-Glx peak, compared with one healthy control subject in the initial study and one neonate with mild HIE in both the studies. They also demonstrated a significantly higher peak-area ratio of alpha-Glx/(creatine and phosphocreatine) on both the initial and follow-up studies. The peak-area ratios in neonates with HIE positively correlated with the Sarnat stage of HIE on both the initial and follow-up studies. Neonates with moderate and severe HIE also showed a consistently higher alpha-Glx peak on both the initial and follow-up studies with the STEAM sequence. CONCLUSION Proton MRS detectability of alpha-Glx is increased in moderate and severe HIE and correlates with the Sarnat stage of HIE.