Maria Concepcion Garcia Otaduy

Creatine in Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Trial

UNLABELLED Creatine supplementation improves glucose tolerance in healthy subjects. PURPOSES The aim was to investigate whether creatine supplementation has a beneficial effect on glycemic control of type 2 diabetic patients undergoing exercise training. METHODS A 12-wk randomized, double-blind, placebo-controlled trial was performed. The patients were allocated to receive either creatine (CR) (5 g·d) or placebo (PL) and were enrolled in an exercise training program. The primary outcome was glycosylated hemoglobin (HbA1c). Secondary outcomes included the area under the curve of glucose, insulin, and C-peptide and insulin sensitivity indexes. Physical capacity, lipid profile, and GLUT-4 protein expression and translocation were also assessed. RESULTS Twenty-five subjects were analyzed (CR: n=13; PL: n=12). HbA1c was significantly reduced in the creatine group when compared with the placebo group (CR: PRE=7.4 ± 0.7, POST=6.4 ± 0.4; PL: PRE=7.5 ± 0.6, POST=7.6 ± 0.7; P=0.004; difference=-1.1%, 95% confidence interval=-1.9% to -0.4%). The delta area under the curve of glucose concentration was significantly lower in the CR group than in the PL group (CR=-7790 ± 4600, PL=2008 ± 7614; P=0.05). The CR group also presented decreased glycemia at times 0, 30, and 60 min during a meal tolerance test and increased GLUT-4 translocation. Insulin and C-peptide concentrations, surrogates of insulin sensitivity, physical capacity, lipid profile, and adverse effects were comparable between the groups. CONCLUSIONS Creatine supplementation combined with an exercise program improves glycemic control in type 2 diabetic patients. The underlying mechanism seems to be related to an increase in GLUT-4 recruitment to the sarcolemma.

Bcl-2 rs956572 Polymorphism is Associated with Increased Anterior Cingulate Cortical Glutamate in Euthymic Bipolar I Disorder

B-cell lymphoma 2 (Bcl-2) is an important regulator of cellular plasticity and resilience. In bipolar disorder (BD), studies have shown a key role for a Bcl-2 gene single-nucleotide polymorphism (SNP) rs956572 in the regulation of intracellular calcium (Ca2+) dynamics, Bcl-2 expression/levels, and vulnerability to cellular apoptosis. At the same time, Bcl-2 decreases glutamate (Glu) toxicity in neural cells. Abnormalities in Glu function have been implicated in BD. In magnetic resonance spectroscopy (MRS) studies, anterior cingulated cortex (ACC) Glu levels have been reported to be increased in bipolar depression and mania, but no study specifically evaluated ACC Glu levels in BD-euthymia. Here, we compared ACC Glu levels in BD-euthymia compared with healthy subjects using 1H-MRS and also evaluated the selective role of the rs956572 Bcl-2 SNP in modulating ACC Glu and Glx (sum of Glu and glutamine) in euthymic-BD. Forty euthymic subjects with BD type I and forty healthy controls aged 18–40 were evaluated. All participants were genotyped for Bcl-2 rs956572 and underwent a 3-Tesla brain magnetic resonance imaging examination including the acquisition of an in vivo PRESS single voxel (2 cm3) 1H-MRS sequence to obtain metabolite levels from the ACC. Euthymic-BD subjects had higher Glu/Cre (creatine) and Glx/Cre compared with healthy controls. The Bcl-2 SNP AA genotype was associated with elevated ACC Glu/Cre and Glx/Cre ratio in the BD group but not in controls. The present study reports for the first time an increase in ACC Glu/Cre and Glx/Cre ratios in BD-euthymia. Also, Bcl-2 AA genotype, previously associated with lower Bcl-2 expression and increase intracellular Ca2+, showed to be associated with increased ACC Glu and Glx levels in euthymic-BD subjects. The present findings reinforce a key role for glutamatergic system dysfunction in the pathophysiology of BD, potentially involving modulatory effects by Bcl-2 in the ACC.

Corpus Callosum Microstructural Changes Correlate with Cognitive Dysfunction in Early Stages of Relapsing-Remitting Multiple Sclerosis: Axial and Radial Diffusivities Approach

The corpus callosum is the largest fiber bundle in the central nervous system and it takes part in several cognitive pathways. It can be affected by multiple sclerosis (MS) early in the disease. DTI is capable of infering the microstructural organization of the white matter. The vectorial analysis of the DTI offers the more specific indices of axial diffusivity (AD) and radial diffusivity (RD), which have shown to be useful to discriminate myelin damage from axon loss, respectively. This study presents DTI results (mean diffusivity (MD), fractional anisotropy (FA), RD, and AD) of 23 relapsing-remitting MS patients and its correlation with cognitive performance. There were 47.8% of cognitive impaired patients (MS CI). We found signs of demyelination, reflected by increased RD, and incipient axon loss, reflected by AD increase, which was slightly higher in the MS CI. The cognitive changes correlated with the DTI parameters, suggesting that loss of complexity in CC connections can impair neural conduction. Thus, cognitive impairment can be related to callosal disconnection, and DTI can be a promising tool to evaluate those changes.

Anterior cingulate Glutamate-Glutamine cycle metabolites are altered in euthymic bipolar I disorder.

Bipolar disorder (BD) has been consistently associated with abnormalities in the Glutamate/GABA-Glutamine cycle. Magnetic resonance spectroscopy (MRS) studies have reported increased brain Glutamate (Glu) and Glx (Glu+Glutamine) in subjects with BD. However, data on separate measures of GABA and Glutamine (Gln) in BD are sparse due to overlapping resonant signals. The development of new sequence methods in the quantification of these metabolites has allowed a better understanding of the Glu/GABA-Gln cycle but data on this field of research remains sparse in BD. Eighty-eight subjects (50 euthymic BD and 38 HC) underwent 3T proton magnetic resonance spectroscopy (1H MRS) in the anterior cingulate cortex (ACC; 2×2×4.5cm(3)) using a two-dimensional JPRESS sequence. GABA, Glutamine (Gln) and Glutamate (Glu) were quantified with the ProFit program. Using image segmentation and known creatine (Cre) concentrations for white and grey matter, metabolite concentrations were calculated for the excited MRS voxel. GABA levels did not differ between groups. Gln level was higher in euthymic BD patients than in healthy controls. The Glu level and Glu/Gln ratio were lower in BD patients than in controls. The use of anticonvulsants was associated with Gln increase but did not affect Glu or Glu/Gln. Neither lithium nor antipsychotic use influenced metabolite levels. The ACC MRS findings indicate that the glutamatergic function in euthymic medicated BD patients is altered relative to controls. Whether this feature is a metabolic signature of euthymic BD subjects should be the focus of future studies.

Multivoxel proton MR spectroscopy in malformations of cortical development.

BACKGROUND AND PURPOSE: Malformations of cortical development (MCD) are traditionally considered as a cause of epilepsy. Our aim was to study patients with focal MCD, by using multivoxel proton MR spectroscopy; we focused not only on the lesion but also on the normal-appearing contralateral side (NACS). Our hypothesis was that the metabolic abnormality extends to the NACS; therefore, it would be inadequate to consider NACS as an internal control. MATERIALS AND METHODS: We studied 16 patients with focal MCD. MR spectroscopy was performed by using a point-resolved spectroscopy sequence technique, including the MCD area and the NACS. In each volume of interest, a smaller volume of interest of 2.25 cm3 centered on the MCD was selected to study the N-acetylaspartate/creatine (NAA/Cr) ratio. In NACS, this ratio was studied by placing a symmetric voxel in comparison with the smaller MCD volume of interest. A control group (n = 30) was also studied to evaluate both white and gray matter by using the same MR spectroscopy protocol. RESULTS: From 16 analyzed volumes of interest with MCD, 9 were composed of gray matter heterotopia and 7 of cortical dysplasia. MR spectroscopy of both MCD lesions and NACS (n = 10) showed decreased NAA/Cr compared with that of the control group. NACS in these patients did not present significant differences regarding NAA/Cr in comparison with the affected side. CONCLUSIONS: MR spectroscopy demonstrated abnormal NAA/Cr in both MCD lesions and NACS in patients harboring focal MCD, giving support to the hypothesis that in MCD metabolic abnormalities extend far away from the limits of the lesion, reaching the contralateral side.

Brain creatine depletion in vegetarians? A cross-sectional 1 H-magnetic resonance spectroscopy ( 1 H-MRS) study

The present cross-sectional study aimed to examine the influence of diet on brain creatine (Cr) content by comparing vegetarians with omnivores. Brain Cr content in the posterior cingulate cortex was assessed by proton magnetic resonance spectroscopy (¹H-MRS). Dietary Cr intake was assessed by 3 d food recalls. Vegetarians had lower dietary Cr intake than omnivores (0.03 (SD 0.01) v. 1.34 (SD 0.62) g/d, respectively; P=0.005). However, vegetarians and omnivores had comparable brain total Cr content (5.999 (SD 0.811) v. 5.917 (SD 0.665) IU, respectively; P=0.77). In conclusion, dietary Cr did not influence brain Cr content in healthy individuals, suggesting that in normal conditions brain is dependent on its own Cr synthesis.

Bimodal Effect of Lithium Plasma Levels on Hippocampal Glutamate Concentrations in Bipolar II Depression: A Pilot Study

Background: The hippocampus has been highly implicated in the pathophysiology of bipolar disorder (BD). Nevertheless, no study has longitudinally evaluated hippocampal metabolite levels in bipolar depression under treatment with lithium. Methods: Nineteen medication-free BD patients (78.9% treatment-naïve and 73.7% with BD type II) presenting an acute depressive episode and 17 healthy controls were studied. Patients were treated for 6 weeks with lithium in an open-label trial. N-acetyl aspartate (NAA), creatine, choline, myo-Inositol, and glutamate levels were assessed in the left hippocampus before (week 0) and after (week 6) lithium treatment using 3T proton magnetic resonance spectroscopy (1H-MRS). The metabolite concentrations were estimated using internal water as reference and voxel segmentation for partial volume correction. Results: At baseline, acutely depressed BD patients and healthy controls exhibited similar hippocampal metabolites concentrations, with no changes after 6 weeks of lithium monotherapy. A significant correlation between antidepressant efficacy and increases in NAA concentration over time was observed. Also, there was a significant positive correlation between the changes in glutamate concentrations over follow-up and plasma lithium levels at endpoint. Mixed effects model analysis revealed a bimodal effect of lithium plasma levels in hippocampal glutamate concentrations: levels of 0.2 to 0.49mmol/L (n=9) were associated with a decrease in glutamate concentrations, whereas the subgroup of BD subjects with “standard” lithium levels (≥0.50 mmol/L; n = 10) showed an overall increase in glutamate concentrations over time. Conclusions: These preliminary results suggest that lithium has a bimodal action in hippocampal glutamate concentration depending on the plasma levels.

DORSAL ANTERIOR CINGULATE LACTATE AND GLUTATHIONE LEVELS IN EUTHYMIC BIPOLAR I DISORDER: 1H-MRS STUDY

Objective: Oxidative stress and mitochondrial dysfunction are 2 closely integrated processes implicated in the physiopathology of bipolar disorder. Advanced proton magnetic resonance spectroscopy techniques enable the measurement of levels of lactate, the main marker of mitochondrial dysfunction, and glutathione, the predominant brain antioxidant. The objective of this study was to measure brain lactate and glutathione levels in bipolar disorder and healthy controls. Methods: Eighty-eight individuals (50 bipolar disorder and 38 healthy controls) underwent 3T proton magnetic resonance spectroscopy in the dorsal anterior cingulate cortex (2x2x4.5cm3) using a 2-D JPRESS sequence. Lactate and glutathione were quantified using the ProFit software program. Results: Bipolar disorder patients had higher dorsal anterior cingulate cortex lactate levels compared with controls. Glutathione levels did not differ between euthymic bipolar disorder and controls. There was a positive correlation between lactate and glutathione levels specific to bipolar disorder. No influence of medications on metabolites was observed. Conclusion: This is the most extensive magnetic resonance spectroscopy study of lactate and glutathione in bipolar disorder to date, and results indicated that euthymic bipolar disorder patients had higher levels of lactate, which might be an indication of altered mitochondrial function. Moreover, lactate levels correlated with glutathione levels, indicating a compensatory mechanism regardless of bipolar disorder diagnosis.

Efficacy and safety of creatine supplementation in childhood-onset systemic lupus erythematosus: a randomized, double-blind, placebo-controlled, crossover trial

Introduction Creatine supplementation has emerged as a promising non-pharmacological therapeutic strategy to counteract muscle dysfunction and low lean mass in a variety of conditions, including in pediatric and rheumatic diseases. The objective of this study was to examine the efficacy and safety of creatine supplementation in childhood systemic lupus erythematosus (C-SLE). Methods C-SLE patients with mild disease activity (n = 15) received placebo or creatine supplementation in a randomized fashion using a crossover, double-blind, repeated-measures design. The participants were assessed at baseline and after 12 weeks in each arm, interspersed by an eight-week washout period. The primary outcomes were muscle function, as assessed by a battery of tests including one-maximum repetition (1-RM) tests, the timed-up-and-go test, the timed-stands test, and the handgrip test. Secondary outcomes included body composition, biochemical markers of bone remodeling, aerobic conditioning, quality of life, and physical capacity. Possible differences in dietary intake were assessed by three 24-hour dietary recalls. Muscle phosphorylcreatine content was measured through phosphorus magnetic resonance spectroscopy (31 P-MRS). The safety of the intervention was assessed by laboratory parameters, and kidney function was measured by 51Cr-EDTA clearance. Additionally, self-reported adverse events were recorded throughout the trial. Results Intramuscular phosphorylcreatine content was not significantly different between creatine and placebo before or after the intervention (creatine-Pre: 20.5 ± 2.6, Post: 20.4 ± 4.1, placebo-Pre: 19.8 ± 2.0; Post: 20.2 ± 3.2 mmol/kg wet muscle; p = 0.70 for interaction between conditions). In addition, probably as a consequence of the lack of change in intramuscular phosphorylcreatine content, there were no significant changes between placebo and creatine for any muscle function and aerobic conditioning parameters, lean mass, fat mass, bone mass, and quality of life scores (p > 0.05). The 51Cr-EDTA clearance was not altered by creatine supplementation and no side effects were noticed. Conclusion A 12-week creatine supplementation protocol at 0.1 g/kg/d is well tolerated and free of adverse effects but did not affect intramuscular phosphorylcreatine, muscle function, free-fat mass or quality of life in non-active C-SLE patients. Trial registration Clinicaltrials.gov number: NCT01217320.

Widespread pH abnormalities in patients with malformations of cortical development and epilepsy: a phosphorus-31 brain MR spectroscopy study.

INTRODUCTION Neuroimaging studies demonstrate that not only the lesions of malformations of cortical development (MCD) but also the normal-appearing parenchyma (NAP) present metabolic impairments, as revealed with (1)H-MRS. We have previously detected biochemical disturbances in MCD lesions with phosphorus-31 magnetic resonance spectroscopy (31P-MRS). Our hypothesis is that pH abnormalities extend beyond the visible lesions. METHODS Three-dimensional 31P-MRS at 3.0 T was performed in 37 patients with epilepsy and MCD, and in 31 matched-control subjects. The patients were assigned into three main MCD subgroups: cortical dysplasia (n=10); heterotopia (n=14); schizencephaly/polymicrogyria (n=13). Voxels (12.5 cm3) were selected in five homologous regions containing NAP: right putamen; left putamen; frontoparietal parasagittal cortex; right centrum semiovale; and left centrum semiovale. Robust methods of quantification were applied, and the intracellular pH was calculated with the chemical shifts of inorganic phosphate (Pi) relative to phosphocreatine (PCr). RESULTS In comparison to controls and considering a Bonferroni adjusted p-value <0.01, MCD patients presented significant reduction in intracellular pH in the frontoparietal parasagittal cortex (6.985±0.022), right centrum semiovale (7.004±0.029), and left centrum semiovale (6.995±0.030), compared to controls (mean values±standard deviations of 7.087±0.048, 7.096±0.042, 7.088±0.045, respectively). Dunnet and Dunn tests demonstrated that the differences in pH values remained statistically significant in all MCD subgroups. No significant differences were found for the putamina. CONCLUSION The present study demonstrates widespread acidosis in the NAP, and reinforces the idea that MCD visible lesions are only the tip of the iceberg.