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1.
The diagnostic performance of 99mTc-methionine single-photon emission tomography in grading glioma preoperatively: a comparison with histopathology and Ki-67 indices.
Rani, N, Singh, B, Kumar, N, Singh, P, Hazari, PP, Jaswal, A, Gupta, SK, Chhabra, R, Radotra, BD, Mishra, AK
Nuclear medicine communications. 2020;(9):848-857
Abstract
OBJECTIVE To characterize glioma preoperatively using quantitative 99mTc-methionine SPECT and comparison with MR-perfusion/spectroscopy and histopatholgical/Ki-67 scoring. METHODS Twenty-nine patients (21M: 8F; mean age 42.3 ± 10.5 years) with clinical and radiological suspicion of glioma assessed by 99mTc-MDM/SPECT and ceMRI. Additionally, 12/29 patients underwent dynamic susceptibility contrast-enhanced (DSCE) MRI and magnetic resonance spectroscopy (MRS) examination. Three patients with benign pathologies were recruited as controls. Histopathological tumor analysis was done in all (n = 29) the patients, and the Ki-67 index was evaluated in 20/29 patients. The target-to-nontarget (T/NT) methionine tumor uptake ratios, normalized cerebral blood volume (nCBV) and metabolites [choline/N-acetyl aspartate (Cho/NAA), Cho/creatine (Cr), Cr/NAA and Cr/Cho) ratios were measured in tumor areas. RESULTS On histopathological analysis, 26/29 patients had glioma (G IV-13; G III-04; G II-09). The mean T/NT ratio in G-II was significantly lower (2.46 ± 2.3) than in G-III (7.13 ± 2.2) and G-IV (5.16 ± 1.2). However, the mean ratio was highest (15.9 ± 6.8) in meningioma (n=3). The T/NT cutoff ratio of 3.08 provided 100% sensitivity, 87.5% specificity for discriminating high-grade glioma (HGG) from low-grade glioma (LGG) disease. Likewise, the nCBV cutoff of 2.43 offered 100% sensitivity and 80% specificity. Only the Cho/NAA cutoff value of greater than 3.34 provided reasonable sensitivity and specificity of 85.7% and 80.0% respectively for this differentiation. T/NT ratio correlated significantly with nCBV and Cho/NAA, Cho/Cr ratios but not with Ki-67. CONCLUSION Quantitative 99mTc-MDM -SPECT provided high sensitivity and specificity to differentiate HGG versus LGG preoperatively and demonstrated a potential role for the differential diagnosis of glial versus nonglial tumors.
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2.
Comparative effects of acute-methionine loading on the plasma sulfur-amino acids in NAC-supplemented HIV+ patients and healthy controls.
Burini, RC, Borges-Santos, MD, Moreto, F, Yu, YM
Amino acids. 2018;(5):569-576
Abstract
In this study, an acute overloading of methionine (MetLo) was used to investigate the trassulfuration pathway response comparing healthy controls and HIV+ patients under their usual diet and dietary N-acetyl-L-cysteine (NAC) supplementation. MetLo (0.1 g Met/kg mass weight) was given after overnight fasting to 20 non-HIV+ control subjects (Co) and 12 HIV+ HAART-treated patients. Blood samples were taken before and after the MetLo in two different 7-day dietary situations, with NAC (1 g/day) or with their usual diet (UD). The amino acids (Met, Hcy, Cys, Tau, Ser, Glu and Gln) and GSH were determined by HPLC and their inflow rate into circulation (plasma) was estimated by the area under the curve (AUC). Under UD, the HIV+ had lower plasma GSH and amino acids (excepting Hcy) and higher oxidative stress (GSSG/GSH ratio), similar remethylation (RM: Me/Hcy + Ser ratio), transmethylation (TM; Hcy/Met ratio) and glutaminogenesis (Glu/Gln ratio), lower transsulfuration (TS: Cys/Hcy + Ser ratio) and Cys/Met ratio and, higher synthetic rates of glutathione (GG: GSH/Cys ratio) and Tau (TG: Tau/Cys ratio). NAC supplementation changed the HIV pattern by increasing RM above control, normalizing plasma Met and TS and, increasing plasma GSH and GG above controls. However, plasma Cys was kept always below controls probably, associatively to its higher consumption in GG (more GSSG than GSH) and TG. The failure of restoring normal Cys by MetLo, in addition to NAC, in HIV+ patients seems to be related to increased flux of Cys into GSH and Tau pathways, probably strengthening the cell-antioxidant capacity against the HIV progression (registered at http://www.clinicaltrials.gov , NCT00910442).
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3.
Comparison of 11C-Methionine and 18F-FDG PET/CT for Staging and Follow-up of Pediatric Lymphoma.
Kaste, SC, Snyder, SE, Metzger, ML, Sandlund, JT, Howard, SC, Krasin, M, Shulkin, BL
Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2017;(3):419-424
Abstract
Methionine transport across plasma membranes occurs via the large amino acid transporter, which is overexpressed in malignant cells, leading to tracer accumulation within tumors. We investigated the uptake of 11C-methionine (11C-MET) in children and young adults with Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL) and compared the biodistribution of 11C-MET PET/CT with that of 18F-FDG PET/CT. Methods: Conducted under an investigational new drug authorization, we prospectively enrolled patients with newly diagnosed HL (n = 19) and NHL (n = 2) onto the Institutional Review Board-approved investigation of 11C-MET PET/CT. After a minimum 4-h fast, patients received 740 MBq/1.7 m2 (maximum, 740 MBq [20 mCi/1.7 m2; maximum, 20 mCi]) of 11C-methionine intravenously. PET/CT was performed 5 min after injection from the vertex to thighs at 3 min per bed position. In a separate session, patients received 5.5 MBq/kg (maximum, 485 MBq [0.15 mCi/kg; maximum, 12 mCi]) of 18F-FDG with imaging initiated approximately 1 h after radiopharmaceutical administration. All studies were reviewed by consensus of 2 senior imaging specialists. The presence of metabolic activity on baseline studies was compared among 17 nodal groups. Results: Eighteen patients (11 male; median age, 15.2 y; age range, 9.5-22.6 y) comprised the study cohort. All had paired 11C-MET PET/CT and 18F-FDG PET/CT studies at diagnosis. At baseline, 3 nodal groups demonstrating discordant metabolic activity by both 18F-FDG PET/CT and 11C-MET PET/CT were Waldeyer's ring, paraaortic region, and the liver. All others were found to have concordant metabolic activity. Normal intense 11C-MET uptake in the pancreas and liver reduced sensitivity for disease detection in these regions. At follow-up, 14 of 15 study pairs had concordant results. Conclusion:11C-MET uptake is elevated in most regions involved with lymphoma at diagnosis and follow-up. Its utility in the abdomen is limited by uptake in normal structures.
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4.
A meta-analysis on the diagnostic performance of (18)F-FDG and (11)C-methionine PET for differentiating brain tumors.
Zhao, C, Zhang, Y, Wang, J
AJNR. American journal of neuroradiology. 2014;(6):1058-65
Abstract
(18)F-FDG-PET has been widely used in patients with brain tumors. However, the reported sensitivity and specificity of (18)F-FDG-PET for brain tumor differentiation varied greatly. We performed this meta-analysis to systematically assess the diagnostic performance of (18)F-FDG-PET in differentiating brain tumors. The diagnostic performance of (11)C-methionine PET was assessed for comparison. Relevant studies were searched in PubMed/MEDLINE, Scopus, and China National Knowledge Infrastructure (until February 2013). The methodologic quality of eligible studies was evaluated, and a meta-analysis was performed to obtain the combined diagnostic performance of (18)F-FDG and (11)C-methionine PET with a bivariate model. Thirty eligible studies, including 5 studies with both (18)F-FDG and (11)C-methionine PET data were enrolled. Pooled sensitivity, pooled specificity, and area under the receiver operating characteristic curve of (18)F-FDG-PET (n = 24) for differentiating brain tumors were 0.71 (95% CI, 0.63-0.78), 0.77 (95% CI, 0.67-0.85), and 0.80. Heterogeneity was found among (18)F-FDG studies. Subsequent subgroup analysis revealed that the disease status was a statistically significant source of the heterogeneity and that the sensitivity in the patients with recurrent brain tumor was markedly higher than those with suspected primary brain tumors. Pooled sensitivity, pooled specificity, and area under the receiver operating characteristic of (11)C-methionine PET (n = 11) were 0.91 (95% CI, 0.85-0.94), 0.86 (95% CI, 0.78-0.92), and 0.94. No significant statistical heterogeneity was found among (11)C-methionine studies. This meta-analysis suggested that (18)F-FDG-PET has limited diagnostic performance in brain tumor differentiation, though its performance may vary according to the status of brain tumor, whereas (11)C-methionine PET has excellent diagnostic accuracy in brain tumor differentiation.
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5.
Simultaneous determination of cystathionine, total homocysteine, and methionine in dried blood spots by liquid chromatography/tandem mass spectrometry and its utility for the management of patients with homocystinuria.
Bártl, J, Chrastina, P, Krijt, J, Hodík, J, Pešková, K, Kožich, V
Clinica chimica acta; international journal of clinical chemistry. 2014;:211-7
Abstract
BACKGROUND Disorders of homocysteine and B-vitamin metabolism represent a significant problem in clinical practice. Establishing the diagnosis requires specialized tests with demanding preanalytical requirements. To advance the detection of patients with these disorders, we developed a method for the simultaneous determination of cystathionine (Cysta), methionine (Met) and total homocysteine (tHcy) in dried blood spots (DBSs). METHODS A punch from a DBS sample was mixed with a solution of isotopically labeled internal standards, and analytes were extracted using methanol/0.1% formic acid/0.5mol/L dithiothreitol. The extract was injected into an LC-MS/MS system operating in MRM mode. RESULTS The analytical performance of the method employing DBS is adequate for its purpose and the type of sample. Compared with Cysta, tHcy and Met plasma levels, our method exhibited a negative bias between -3.8% and -42.2% due to the lower concentrations of these analytes in erythrocytes. The tHcy level and the Met/Cysta ratio in DBS enabled the clear detection of 12 patients with disorders of transsulfuration and with genetic and nutritional remethylation defects. CONCLUSIONS The ease of collecting and transporting DBS samples may advance diagnostic procedures in patients with neuropsychiatric disorders and thromboembolism. Consequently, this approach may facilitate detection and simplify the monitoring of patients with homocystinuria.
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6.
Oral supplementation with a nutraceutical containing Echinacea, methionine and antioxidant/immunostimulating compounds in patients with cutaneous viral warts.
Cassano, N, Ferrari, A, Fai, D, Pettinato, M, Pellè, S, Del Brocco, L, Ligori, P, Romano, I, Curia, S, Carbonara, M, et al
Giornale italiano di dermatologia e venereologia : organo ufficiale, Societa italiana di dermatologia e sifilografia. 2011;(3):191-5
Abstract
AIM: The aim of thos paper was to determine the effect of oral supplementation (OS) with a nutraceutical, containing methionine, Echinacea, zinc, probiotics and other antioxidant and immunostimulating compounds, on the response of cutaneous warts to conventional standard therapy (CST). METHODS This was an open-label study in adults and adolescents aged 14 years or more and with a body weight ≥40 kg, who had at least one cutaneous viral wart. Eligible patients were consecutively allocated to CST (topical therapy with a preparation containing salicylic acid and lactic acid or liquid nitrogen cryotherapy) alone or CST combined with nutraceutical OS for 4 months. RESULTS A total of 172 patients were enrolled: 83 received CST alone and 89 CST+OS. During the 6-month observation period, a statistically significant reduction of the mean number of warts was obtained in each treatment group and subgroup. The addition of nutraceutical OS was associated with a significantly lower number of warts at 6 months as compared to CST alone. Complete remission was obtained in 54.5% and 86% of patients in the CST group and CST+OS arm, respectively (P<0.001). The influence of the nutraceutical on the response rate appeared to be more prominent in the subgroup of patients treated with topical therapy. The development of new warts during the study period occurred significantly less frequently with CST+OS compared to CST (9% versus 25%; P=0.004). No adverse events possibly related to the nutraceutical administration were observed. CONCLUSION Our pilot experience seems to suggest that nutraceutical OS is safe and beneficial in patients with cutaneous warts, and capable of enhancing the response to CST.
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7.
The functional Val158Met polymorphism of COMT predicts interindividual differences in brain alpha oscillations in young men.
Bodenmann, S, Rusterholz, T, Dürr, R, Stoll, C, Bachmann, V, Geissler, E, Jaggi-Schwarz, K, Landolt, HP
The Journal of neuroscience : the official journal of the Society for Neuroscience. 2009;(35):10855-62
Abstract
Individual patterns of the electroencephalogram (EEG) in wakefulness and sleep are among the most heritable traits in humans, yet distinct genetic and neurochemical mechanisms underlying EEG phenotypes are largely unknown. A functional polymorphism in the gene encoding catechol-O-methyltransferase (COMT), an enzyme playing an important role in cortical dopamine metabolism, causes a common substitution of methionine (Met) for valine (Val) at codon 158 of COMT protein. Val allele homozygotes exhibit higher COMT activity and lower dopaminergic signaling in prefrontal cortex than Met/Met homozygotes. Evidence suggests that this polymorphism affects executive functions in healthy individuals. We hypothesized that it also modulates functional aspects of EEG in wakefulness and sleep. EEG recordings were conducted twice on separate occasions in 10 Val/Val and 12 Met/Met allele carriers (all men) in wakefulness, and in baseline and recovery sleep before and after 40 h prolonged waking. During sleep deprivation, subjects received placebo and modafinil in randomized, cross-over manner. We show that the Val158Met polymorphism predicts stable and frequency-specific, interindividual variation in brain alpha oscillations. Alpha peak frequency in wakefulness was 1.4 Hz slower in Val/Val genotype than in Met/Met genotype. Moreover, Val/Val allele carriers exhibited less 11-13 Hz activity than Met/Met homozygotes in wakefulness, rapid-eye-movement (REM) sleep, and non-REM sleep. This difference was resistant against the effects of sleep deprivation and modafinil. The data demonstrate that mechanisms involving COMT contribute to interindividual differences in brain alpha oscillations, which are functionally related to executive performance such as counting tendency on a random number generation task in young adults.
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8.
Role of the sulfur atom on the reactivity of methionine toward OH radicals: comparison with norleucine.
Francisco-Marquez, M, Galano, A
The journal of physical chemistry. B. 2009;(14):4947-52
Abstract
Density functional theory has been used to model the OH reaction with Gly-Met-Gly and Gly-Nle-Gly tripeptides. The first one is predicted to be about 100 times faster than the second one. Therefore, if a methionine fragment is replaced by norleucine, the overall reactivity of the peptide toward free radicals is expected to be significantly reduced, which is in agreement with previous experimental findings. Since the most reactive sites were found to be located in the central backbone for Nle and in the terminal fragment of the side chain for Met, this decrease is expected to be even more critical for large-sized free radicals. The S atom seems to activate not only those alkyl sites next to it but also those located an odd number of bonds apart. In addition the viability of different paths explaining the formation of methionine sulfoxide has been tested, and it is proposed that this process involves the formation of R-SO radical and formaldehyde. The results from the present work offer an explanation to the role of sulfur atom on the reactivity of methionine toward free radicals. They also support the preponderant role of Met35 on the development of the Alzheimer disease.
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9.
Relationship of the Met allele of the brain-derived neurotrophic factor Val66Met polymorphism to memory after aneurysmal subarachnoid hemorrhage.
Vilkki, J, Lappalainen, J, Juvela, S, Kanarek, K, Hernesniemi, JA, Siironen, J
Neurosurgery. 2008;(2):198-203; discussion 203
Abstract
OBJECTIVE The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism has been shown to be related to variability in episodic memory. We studied whether the Met allele is associated with poor learning and memory in survivors of aneurysmal subarachnoid hemorrhage (SAH). METHODS Ninety-six patients were examined with a neuropsychological test battery approximately 1 year after SAH. Their deoxyribonucleic acid samples were genotyped for the BDNF Val66Met polymorphism. The Met carriers were compared to the Val/Val homozygous patients on the test performances. RESULTS In the total sample, there was no difference between the genotype groups. However, among the patients with no cerebral infarction, the Met carriers had inferior learning and memory performance than the Val/Val homozygotes, but the groups did not differ on the nonmemory test performances. The patients with left and bilateral infarctions had deficits in verbal memory, which may have concealed the effect of the BDNF Val66Met polymorphism on memory in the total sample. CONCLUSION As a whole, the BDNF Val66Met polymorphism was not associated with learning and memory performance in patients recovering from SAH. However, the Met allele might predict poor memory function among patients with SAH not complicated by a cerebral infarction. These findings support earlier reports of an association between the Met allele and low memory performance. Longitudinal studies comparing functional recovery from SAH between Met and Val/Val patients without cerebral infarctions are warranted.
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10.
Brain-derived neurotrophic factor Val66Met and psychiatric disorders: meta-analysis of case-control studies confirm association to substance-related disorders, eating disorders, and schizophrenia.
Gratacòs, M, González, JR, Mercader, JM, de Cid, R, Urretavizcaya, M, Estivill, X
Biological psychiatry. 2007;(7):911-22
Abstract
BACKGROUND There is an increasing recognition that the pathophysiology of mental disorders could be the result of deregulation of synaptic plasticity with alterations of neurotrophins. The valine (Val)66-to-methionine (Met) variant, located in the pro brain-derived neurotrophic factor (BDNF) sequence, has been extensively studied through linkage and association approaches in several psychiatric disorders. METHODS We performed a meta-analysis restricted to individual case-control studies in different categories of mental disorders and BDNF Val66Met polymorphism. We included data from 39 case-control studies encompassing psychiatric phenotypes: eating disorders, substance-related disorders, mood disorders, and schizophrenia, among others. RESULTS The association of Val66Met was confined to three diagnoses: substance-related disorders, eating disorders, and schizophrenia. The Val/Met and the Met/Met genotypes increase the risk for eating disorders up to 33%, while these same genotypes confer a 21% protective effect in substance-related disorders. The homozygous carriers Met/Met showed a 19% increased risk of schizophrenia with respect to the heterozygous state. CONCLUSIONS The study confirms the association of Val66Met to substance-related disorders, eating disorders, and schizophrenia. It remains to be determined if other variants in tight linkage disequilibrium with Val66Met could configure an extended functional haplotype that would explain observed discrepancies in risk estimations across studies.