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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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High plasma glutamate and low glutamine-to-glutamate ratio are associated with type 2 diabetes: Case-cohort study within the PREDIMED trial.
Liu, X, Zheng, Y, Guasch-Ferré, M, Ruiz-Canela, M, Toledo, E, Clish, C, Liang, L, Razquin, C, Corella, D, Estruch, R, et al
Nutrition, metabolism, and cardiovascular diseases : NMCD. 2019;(10):1040-1049
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BACKGROUND AND AIMS Glutamate, glutamine are involved in energy metabolism, and have been related to cardiometabolic disorders. However, their roles in the development of type-2 diabetes (T2D) remain unclear. The aim of this study was to examine the effects of Mediterranean diet on associations between glutamine, glutamate, glutamine-to-glutamate ratio, and risk of new-onset T2D in a Spanish population at high risk for cardiovascular disease (CVD). METHODS AND RESULTS The present study was built within the PREDIMED trial using a case-cohort design including 892 participants with 251 incident T2D cases and 641 non-cases. Participants (mean age 66.3 years; female 62.8%) were non diabetic and at high risk for CVD at baseline. Plasma levels of glutamine and glutamate were measured at baseline and after 1-year of intervention. Higher glutamate levels at baseline were associated with increased risk of T2D with a hazard ratio (HR) of 2.78 (95% CI, 1.43-5.41, P for trend = 0.0002). In contrast, baseline levels of glutamine (HR: 0.64, 95% CI, 0.36-1.12; P for trend = 0.04) and glutamine-to-glutamate ratio (HR: 0.31, 95% CI, 0.16-0.57; P for trend = 0.0001) were inversely associated with T2D risk when comparing extreme quartiles. The two Mediterranean diets (MedDiet + EVOO and MedDiet + mixed nuts) did not alter levels of glutamine and glutamate after intervention for 1 year. However, MedDiet mitigated the positive association between higher baseline plasma glutamate and T2D risk (P for interaction = 0.01). CONCLUSION Higher levels of glutamate and lower levels of glutamine were associated with increased risk of T2D in a Spanish population at high risk for CVD. Mediterranean diet might mitigate the association between the imbalance of glutamine and glutamate and T2D risk. This trial is registered at http://www.controlled-trials.com, ISRCTN35739639.
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Utility of Imaging-Based Biomarkers for Glutamate-Targeted Drug Development in Psychotic Disorders: A Randomized Clinical Trial.
Javitt, DC, Carter, CS, Krystal, JH, Kantrowitz, JT, Girgis, RR, Kegeles, LS, Ragland, JD, Maddock, RJ, Lesh, TA, Tanase, C, et al
JAMA psychiatry. 2018;(1):11-19
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IMPORTANCE Despite strong theoretical rationale and preclinical evidence, several glutamate-targeted treatments for schizophrenia have failed in recent pivotal trials, prompting questions as to target validity, compound inadequacy, or lack of target engagement. A key limitation for glutamate-based treatment development is the lack of functional target-engagement biomarkers for translation between preclinical and early-stage clinical studies. We evaluated the utility of 3 potential biomarkers-ketamine-evoked changes in the functional magnetic imaging (fMRI) blood oxygen level-dependent response (pharmacoBOLD), glutamate proton magnetic resonance spectroscopy (1H MRS), and task-based fMRI-for detecting ketamine-related alterations in brain glutamate. OBJECTIVE To identify measures with sufficient effect size and cross-site reliability to serve as glutamatergic target engagement biomarkers within early-phase clinical studies. DESIGN, SETTING, AND PARTICIPANTS This randomized clinical trial was conducted at an academic research institution between May 2014 and October 2015 as part of the National Institute of Mental Health-funded Fast-Fail Trial for Psychotic Spectrum Disorders project. All raters were blinded to study group. Healthy volunteers aged 18 to 55 years of either sex and free of significant medical or psychiatric history were recruited from 3 sites. Data were analyzed between November 2015 and December 2016. INTERVENTIONS Volunteers received either sequential ketamine (0.23 mg/kg infusion over 1 minute followed by 0.58 mg/kg/h infusion over 30 minutes and then 0.29 mg/kg/h infusion over 29 minutes) or placebo infusions. MAIN OUTCOMES AND MEASURES Ketamine-induced changes in pharmacoBOLD, 1H MRS, and task-based fMRI measures, along with symptom ratings. Measures were prespecified prior to data collection. RESULTS Of the 65 volunteers, 41 (63%) were male, and the mean (SD) age was 31.1 (9.6) years; 59 (91%) had at least 1 valid scan. A total of 53 volunteers (82%) completed both ketamine infusions. In pharmacoBOLD, a highly robust increase (Cohen d = 5.4; P < .001) in fMRI response was observed, with a consistent response across sites. A smaller but significant signal (Cohen d = 0.64; P = .04) was also observed in 1H MRS-determined levels of glutamate+glutamine immediately following ketamine infusion. By contrast, no significant differences in task-activated fMRI responses were found between groups. CONCLUSIONS AND RELEVANCE These findings demonstrate robust effects of ketamine on pharmacoBOLD across sites, supporting its utility for definitive assessment of functional target engagement. Other measures, while sensitive to ketamine effects, were not sufficiently robust for use as cross-site target engagement measures. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT02134951.
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Glutamatergic medication in the treatment of obsessive compulsive disorder (OCD) and autism spectrum disorder (ASD) - study protocol for a randomised controlled trial.
Häge, A, Banaschewski, T, Buitelaar, JK, Dijkhuizen, RM, Franke, B, Lythgoe, DJ, Mechler, K, Williams, SC, Dittmann, RW, ,
Trials. 2016;(1):141
Abstract
BACKGROUND Compulsivity is a cross-disorder trait underlying phenotypically distinct psychiatric disorders that emerge in childhood or adolescence. Despite the effectiveness of serotonergic compounds in the treatment of obsessive-compulsive disorder, treatment-resistant symptoms remaining in 40 to 60 % of patients present a pressing clinical problem. There are currently no medications that effectively treat the core impairments of autism spectrum disorder. There is an urgent need for the development of conceptually novel pharmacological strategies. Agents targeting glutamate neurotransmission, such as memantine, represent promising candidates. This proof-of-concept clinical study will allow pilot-testing of memantine for both clinical effectiveness and tolerability/safety. Memantine is an N-methyl-D-aspartate receptor antagonist, approved for the treatment of Alzheimer's dementia in a number of countries. METHODS/DESIGN This 12-week study has an add-on, randomised, double-blind, placebo-controlled design of treatment with memantine, including an up-titration phase (forced flexible dose design, 5-15 mg/day), in patients aged 6-17 years and 9 months with obsessive-compulsive disorder or autism spectrum disorder. It is planned to include patients with obsessive-compulsive disorder (N = 50) or autism spectrum disorder (N = 50) across four centres in three European countries. Patients will be randomly assigned to memantine or placebo in a 1:1 ratio. Primary objectives are the investigation of the effectiveness of memantine in paediatric patients for improving symptoms of compulsivity (primary outcome measure: total score on the Children's Yale-Brown Obsessive-Compulsive Scale) and to explore its tolerability and safety. Secondary objectives are to explore the effects of memantine at the level of structure, function and biochemistry of the fronto-striatal circuits, and to collect blood for genetic analyses and biomarkers. Tertiary objectives are to explore the role of new candidate genes and pathways for compulsivity by linking genes to clinical phenotypes, response to treatment, neurocognitive test performance, and key structural and functional neuroimaging measures of the fronto-striatal circuits and to explore biomarkers/proteomics for compulsivity traits. DISCUSSION This study is part of the large, translational project TACTICS ( http://www.tactics-project.eu/ ) that is funded by the European Union and investigates the neural, genetic and molecular factors involved in the pathogenesis of compulsivity. Its results will provide clinically relevant solid information on potential new mechanisms and medication treatment in obsessive-compulsive and autism spectrum disorders. TRIAL REGISTRATION EudraCT Number: 2014-003080-38 , date of registration: 14 July 2014.
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GLUTAMICS--a randomized clinical trial on glutamate infusion in 861 patients undergoing surgery for acute coronary syndrome.
Vidlund, M, Håkanson, E, Friberg, O, Juhl-Andersen, S, Holm, J, Vanky, F, Sunnermalm, L, Borg, JO, Sharma, R, Svedjeholm, R
The Journal of thoracic and cardiovascular surgery. 2012;(4):922-930.e7
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OBJECTIVE Glutamate has been claimed to protect the heart from ischemia and to facilitate metabolic and hemodynamic recovery after ischemia. The GLUTAmate for Metabolic Intervention in Coronary Surgery trial investigated whether an intravenous glutamate infusion given in association with surgery for acute coronary syndrome could reduce mortality and prevent or mitigate myocardial injury and postoperative heart failure. METHODS In the present prospective, triple-center, double-blind study, 861 patients undergoing surgery for acute coronary syndrome were randomly assigned to an intravenous infusion of glutamate (n = 428) or saline (n = 433) perioperatively. RESULTS The incidence of the primary endpoint--a composite of 30-day mortality, perioperative myocardial infarction, and left ventricular heart failure at weaning from cardiopulmonary bypass-was 7.3% versus 5.8% (P = .41) in the glutamate and control groups, respectively. Patients with left ventricular failure at weaning from cardiopulmonary bypass had a shorter median intensive care unit stay (25 vs 92 hours; P = .02) if they were treated with glutamate. In patients with unstable angina (Canadian Cardiovascular Society class IV) undergoing isolated coronary artery bypass grafting (n = 458), the incidence of severe circulatory failure according to the prespecified criteria was significantly lower in the glutamate group (1.3% vs 6.9%; P = .004). On multivariate analysis, glutamate infusion was associated with a reduced risk of developing severe circulatory failure (odds ratio, 0.17; 95% confidence interval, 0.04-0.72; P = .02). A relative risk reduction exceeding 50% for developing severe circulatory failure was seen in most risk groups undergoing isolated coronary artery bypass grafting, with those with diabetes a notable exception. CONCLUSIONS The primary endpoint did not differ significantly between the groups. The secondary outcomes and post hoc analyses warrant additional studies with regard to the potential beneficial effect of glutamate on postischemic myocardial recovery.
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Memantine in patients with Parkinson's disease dementia or dementia with Lewy bodies: a double-blind, placebo-controlled, multicentre trial.
Aarsland, D, Ballard, C, Walker, Z, Bostrom, F, Alves, G, Kossakowski, K, Leroi, I, Pozo-Rodriguez, F, Minthon, L, Londos, E
The Lancet. Neurology. 2009;(7):613-8
Abstract
BACKGROUND Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are common forms of dementia that substantially affect quality of life. Currently, the only treatment licensed for PDD is rivastigmine, and there are no licensed treatments for DLB. We aimed to test the safety and efficacy of the N-methyl D-aspartate (NMDA) receptor antagonist memantine in patients with PDD or DLB. METHODS We did a parallel-group, 24-week, randomised controlled study of memantine (20 mg per day) versus placebo at four psychiatric and neurological outpatient clinics in Norway, Sweden, and the UK during 2005-08. Patients were included if they fulfilled the UK Parkinson's Disease Society Brain Bank clinical diagnostic criteria for Parkinson's disease (PD) and developed dementia according to the Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM IV) criteria at least 1 year after the onset of motor symptoms (PDD) or met the revised consensus operationalised criteria for DLB. Patients were assigned to a computer-generated randomisation list. All physicians who had contact with patients were masked to treatment allocation. The primary outcome measure was clinical global impression of change (CGIC), which ranged from 1 to 7 points, and a low score means a better outcome. Analysis was by intention to treat based on the last observation carried forward. This trial is registered, number ISRCTN89624516. FINDINGS 72 patients with PDD or DLB were randomly assigned and started treatment: 34 with memantine and 38 with placebo. 56 (78%) completed the study. All withdrawals were owing to adverse events, but the proportion of withdrawals was similar in both groups. At week 24 the patients in the memantine group had better CGIC scores than those taking placebo (mean difference 0.7, 95% CI 0.04-1.39; p=0.03). With the exception of improved speed on attentional tasks in the memantine group (a quick test of cognition [AQT] form: difference 12.4, 95% CI 6.0-30.9; p=0.004), there were no significant differences between the groups in secondary outcome measures. INTERPRETATION Patients with DLB or PDD might benefit from treatment with memantine, which was well tolerated. Large-scale studies are now required to confirm our preliminary findings. FUNDING The Western Norway Regional Health Authority; H Lundbeck A/S.