Measurement of brain metabolites in patients with type 2 diabetes and major depression using proton magnetic resonance spectroscopy.

Type 2 diabetes and major depression are disorders that are mutual risk factors and may share similar pathophysiological mechanisms. To further understand these shared mechanisms, the purpose of our study was to examine the biochemical basis of depression in patients with type 2 diabetes using proton MRS. Patients with type 2 diabetes and major depression (n=20) were scanned along with patients with diabetes alone (n=24) and healthy controls (n=21) on a 1.5 T MRI/MRS scanner. Voxels were placed bilaterally in dorsolateral white matter and the subcortical nuclei region, both areas important in the circuitry of late-life depression. Absolute values of myo-inositol, creatine, N-acetyl aspartate, glutamate, glutamine, and choline corrected for CSF were measured using the LC-Model algorithm. Glutamine and glutamate concentrations in depressed diabetic patients were significantly lower (p<0.001) in the subcortical regions as compared to healthy and diabetic control subjects. Myo-inositol concentrations were significantly increased (p<0.05) in diabetic control subjects and depressed diabetic patients in frontal white matter as compared to healthy controls. These findings have broad implications and suggest that alterations in glutamate and glutamine levels in subcortical regions along with white matter changes in myo-inositol provide important neurobiological substrates of mood disorders.     

Cortical glutathione levels in young people with bipolar disorder: a pilot study using magnetic resonance spectroscopy

Rationale

Glutathione (GSH) is a key scavenger for cellular free radicals, and patients with bipolar disorder may have lowered GSH levels in plasma and in post-mortem brain tissue.

Objectives

The objective of the current study was to use magnetic resonance spectroscopy (MRS) to measure cortical GSH levels in young people with bipolar disorder to determine if lowered GSH might be a useful biomarker of vulnerability to the illness.

Methods

We studied 13 patients with DSM-IV bipolar disorder and 11 healthy age-matched controls using proton MRS in conjunction with the SPECIAL acquisition technique. Voxels were placed in prefrontal and occipital cortex. All patients were clinically euthymic at the time of study and unmedicated. GSH and other relevant neurometabolites were measured relative to creatinine.

Results

There was no difference in GSH levels between bipolar participants and controls in either prefrontal or occipital cortex. Similarly, participants showed no difference from controls in other measured cortical metabolites including γ-aminobutyric acid, glutamate and N-acetylaspartate.

Conclusions

This pilot study suggests that levels of cortical GSH are unlikely to be a useful trait biomarker of bipolar disorder in young people with a history of relatively mild mood instability at an early stage of illness. Lowered GSH levels may be relevant to bipolar pathophysiology in more severely ill patients, particular those with significant current mood disturbance.     

Monitoring pharmacokinetics of anticancer drugs: non-invasive investigation using magnetic resonance spectroscopy

Magnetic resonance spectroscopy (MRS) offers the unique advantage of detecting, identifying and quantifying chemicals deep within the living body in a totally non-invasive manner. In studies on pharmacology and toxicology of anticancer drugs, MRS and the closely related technique magnetic resonance imaging (MRI) have many uses. MRS in particular, despite its low sensitivity, offers unique insights into pharmacokinetics (the changing concentration of the drug at its site of action) which can be monitored, and metabolism (both activation and detoxification) can be detected in real time. This review considers some recent work on (19)F, (31)P, (1)H and (13)C MRS of anticancer drugs. Future possibilities for (13)C MRS and (1)H MRS studies of drugs and their metabolites are considered in detail.     

Microcoil nuclear magnetic resonance spectroscopy

In comparison with most analytical chemistry techniques, nuclear magnetic resonance has an intrinsically low sensitivity, and many potential applications are therefore precluded by the limited available quantity of certain types of sample. In recent years, there has been a trend, both commercial and academic, towards miniaturization of the receiver coil in order to increase the mass sensitivity of NMR measurements. These small coils have also proved very useful in coupling NMR detection with commonly used microseparation techniques. A further development enabled by small detectors is parallel data acquisition from many samples simultaneously, made possible by incorporating multiple receiver coils into a single NMR probehead. This review article summarizes recent developments and applications of “microcoil” NMR spectroscopy.     

Neurochemical effects of olanzapine in first-hospitalization manic adolescents: a proton magnetic resonance spectroscopy study.

We used proton magnetic resonance spectroscopy (1H MRS) to compare the in vivo effects of olanzapine on prefrontal N-acetyl-aspartate (NAA) levels in treatment remitters and nonremitters. Secondary aims of this study were to identify neurochemical predictors of successful olanzapine treatment and other neurochemical effects of olanzapine. In all, 20 adolescents admitted for their first hospitalization for bipolar disorder, type I, manic or mixed and 10 demographically matched healthy subjects were recruited. Manic adolescents were treated with olanzapine monotherapy and scanned at three time points (N = 19). Medial and left and right lateral ventral prefrontal NAA, choline, creatine/phosphocreatine, myo-inositol, and glutamate/glutamine were measured at baseline, prior to receiving medication, and on days 7 and 28 of treatment. Healthy subjects did not receive medication but underwent 1H MRS scans at the same time points to assess for normal variability in metabolites over time. Although there was no overall increase in NAA in manic adolescents following 28 days of treatment with olanzapine, olanzapine remitters (N = 11, 58%) exhibited a greater increase in medial ventral prefrontal NAA compared with nonremitters (N = 8, 42%, p = 0.006). Specifically, from baseline to end point, NAA levels decreased in nonremitters (p = 0.03) and increased in remitters (p = 0.05). Manic adolescents treated with olanzapine had an increase from baseline to day 7 in medial (p = 0.002) and right lateral (p = 0.02) ventral prefrontal choline. Baseline medial ventral prefrontal choline was greater in olanzapine remitters than in nonremitters (p = 0.001). Successful treatment of mania with olanzapine may lead to increased ventral prefrontal neuronal viability and/or function as compared to unsuccessful treatment with olanzapine. Additionally, olanzapine-induced increases in choline may lead to alteration of abnormalities in cell membrane metabolism or second messenger pathways that are thought to be involved in the pathophysiology of bipolar disorder.     

A study of catecholamine nucleotide complexes by nuclear magnetic resonance spectroscopy

Summary The direct chemical interaction of catecholamines with adenine nucleotides has been examined using the technique of nuclear magnetic resonance spectroscopy. Preferential stabilization of the alpha and beta carbons of the side chain of epinephrine has been demonstrated by selective changes in the relaxation times of the protons attached to these carbons. By varying the concentrations of amine and nucleotide, it has been shown that at pH 5.6, three molecules of epinephrine can interact with one molecule of ATP and one molecule of epinephrine can interact with one molecule of AMP. An additional catecholamine molecule may be attached to the adenine nucleotide complexes at a higher pH. The complex appears to involve an ionic bond between the catecholamine nitrogen and the phosphate moiety of the nucleotide and a hydrogen bond between the beta hydroxyl group of the catecholamine and a phosphate oxygen. The very small preferential stabilization of the side chain carbons of dopamine in the presence of ATP indicates that the beta hydroxyl group of the catecholamine plays a role in the interaction.With 4 Figures in the TextDedicated to Professor Otto Krayer on the occasion of his 65th birthday.A portion of this work was presented at the 1st International Pharmacological Meetings, Stockholm, 1961.This work was supported by grants GM-09591 and NB-02947 from the National Institutes of Health, grants GB-578 and GB-19296 from the National Science Foundation and U.S. Air Force Contract 41(657)-414.We wish to acknowledge the assistance of Dr. Peter Pappas during the initial stages of this investigation, and the assistance of Mrs. Kriemhild Koenig and Miss Norma Wade.     

Interaction of caffeine with L-tryptophan: study by 1H nuclear magnetic resonance spectroscopy

The interaction of caffeine with L-tryptophan was investigated in aqueous solution adjusted to an ionic strength of 0.20, at pH 6.2, by using 1H NMR spectroscopy. Caffeine interacted with L-tryptophan at a molar ratio of 1:1 by parallel stacking. The thermodynamic parameters obtained for the complexation were as follows: delta G degree = -1.70 kcal/mol at 25 degrees C (K = 17.6 M-1), delta H degree = -3.7 kcal/mol, delta S degree = -6.7 eu. It was found that the driving force for parallel stacking is a combination of electrostatic, polarization, and dispersion interactions, and the contribution of hydrophobic bonding is not large. A possible stacking mode is postulated based on the complexation shifts and pi-electron charge distributions of caffeine and L-tryptophan.     

Quality assessment of unfractionated heparin using 1H nuclear magnetic resonance spectroscopy

Due to problems, especially anaphylactoid reactions, raised by impure unfractionated heparin the quality assessment of heparin has to be reconsidered. Neither the USP nor the European Pharmacopoeia are able to guarantee the purity of heparin, i.e., the limitation of oversulfated chondroitin sulfate (OSCS) which was found to be the reason for the allergic adverse effects. In the first run the regulatory authorities ask for (1)H NMR spectroscopic and capillary electrophoretic measurements in order to characterize the impurity profile of heparin. Using an optimized (1)H NMR method the limit of detection for OSCS was found to be 0.1%. In addition, it is possible to reliably quantify both OSCS and dermatan sulfate (DS), the latter being an indicator of poor purification of the unfractionated heparin. Screening of more than 100 heparin samples collected from international markets revealed a high number of samples containing substantial amounts of DS and a number of samples containing OSCS in an amount higher than 0.1%.     

Structural analysis of proteins in living eukaryotic cells using magnetic resonance spectroscopy

Three-dimensional structures of proteins are often critical in understanding proteins functions. However, structures or states of proteins in cells undergo dynamical changes in response to interactions with other proteins and/or biological molecules. In addition, post-translational modification such as phosphorylation, methylation and ubiquitination can drastically change the structure and hence the properties of proteins. Therefore, to precisely correlate structure data of proteins with cell biology data, the structure information should be collected in living cells preferably at atomic level. In addition, as numerous biomolecules are packed into limited space, the concentration of macromolecules is substantially high in cells. Such crowded environment of the cell interior can markedly change proteins behavior, affecting biochemistry and biophysics of the proteins, which is so-called "Macromolecular Crowding Effect". To figure out protein behavior inside cells, which may be missed in in vitro studies, we are developing NMR and ESR methodologies to analyze protein structure and dynamics inside eukaryotic cultured cells. In this paper, in-cell NMR/ESR studies performed on HeLa cells and Xenopus oocytes are presented.     

Differentiation of lung cancer and radiation fibrosis using magnetic resonance images: a case study

We used magnetic resonance imaging to differentiate residual and recurrent lung cancer from the surrounding radiation pulmonary fibrosis in a 62-year-old patient. The cancer's signal intensity was greater than the fibrotic lung tissue's intensity in an ECG-gated image with relatively short repetition and echo times and, also, in images with long repetition and echo times.     

Early increase in marker of neuronal integrity with antidepressant treatment of major depression: 1H-magnetic resonance spectroscopy of N-acetyl-aspartate

Increasing interest surrounds potential neuroprotective or neurotrophic actions of antidepressants. While growing evidence points to important early clinical and neuropsychological effects of antidepressants, the time-course of any effect on neuronal integrity is unclear. This study used magnetic resonance spectroscopy to assess effects of short-term treatment with escitalopram on N-acetyl-aspartate (NAA), a marker of neuronal integrity. Thirty-nine participants with major depression were randomly assigned to receive either 10 mg escitalopram or placebo daily in a double-blind, parallel group design. On the seventh day of treatment, PRESS data were obtained from a 30×30×20 mm voxel placed in medial frontal cortex. Age and gender-matched healthy controls who received no treatment were also scanned. Levels of NAA were significantly higher in patients treated with escitalopram than in either placebo-treated patients (p<0.01) or healthy controls (p<0.01). Our findings are consistent with the proposition that antidepressant treatment in depressed patients can produce early changes in neuronal integrity.     

Determination of scutellarin in breviscapine preparations using quantitative proton nuclear magnetic resonance spectroscopy

The objective of the present study was to develop the selection criteria of proton signals for the determination of scutellarin using quantitative nuclear magnetic resonance (qNMR), which is the main bioactive compound in breviscapine preparations for the treatment of cerebrovascular disease. The methyl singlet signal of 3-(trimethylsilyl)propionic-2,2,3,3-d₄ acid sodium salt was selected as the internal standard for quantification. The molar concentration of scutellarin was determined by employing different proton signals. To obtain optimum proton signals for the quantification, different combinations of proton signals were investigated according to two selection criteria: the recovery rate of qNMR method and quantitative results compared with those obtained with ultra-performance liquid chromatography. As a result, the chemical shift of H-2′ and H-6′ at δ 7.88 was demonstrated as the most suitable signal with excellent linearity range, precision, and recovery for determining scutellarin in breviscapine preparations from different manufacturers, batch numbers, and dosage forms. Hierarchical cluster analysis was employed to evaluate the determination results. The results demonstrated that the selection criteria of proton signals established in this work were reliable for the qNMR study of scutellarin in breviscapine preparations.     

脑梗死后活体脑代谢的磁共振定域波谱研究

目的：探讨脑梗死后脑梗死区及对侧大脑半球相应区域感兴趣（VOI）的代谢变化和高糖对各区域代谢的影响。方法：采用磁共振定域波谱技术（MRS），在同一活体上分别连续测定梗死区与对照区的^1H-MRS。结果：梗死区胆碱（Cho)、磷酸肌酸／肌酸（Pcr/Cr)、N－乙酰天门冬氨酸（NAA）强度均低于对照区，NAA在梗死急性期变化明显，加用高糖30分种后可见梗死区原有乳酸（Lac)信号成倍增加（Lac/NAA-1.0873)，随着时间推移逐渐恢复（Lac/NAA-0.3013）。结论：（1）采用MRS定域谱技术可更精确、更客观地检测各VOI区代谢变化。（2）脑梗死区NAA、Cho、Cr均有下降，而NAA下降更为明显，非梗死半球各指标无明显变化，NAA可塑作为MRS早期诊断脑梗死的有效指标。（3）高糖可加剧脑梗死区的病理代谢导致Lac积聚，及时停用高糖可望缓解Lac积聚状态。本文客观地直接展示了高糖加剧梗死区病理代谢的全过程，为改进临床治疗提供了直接有力的证据。     

Effect of intestinal microflora on the urinary metabolic profile of rats: a 1 H-nuclear magnetic resonance spectroscopy study

1. Analysis of urine by 1 H-nuclear magnetic resonance (NMR) spectroscopy is used to detect biochemical disturbances predictive of toxicological changes. Recent studies, using 1 H-NMR spectroscopy have suggested that Alderley Park rats can be classified as hippuric acid (HA) or m -(hydroxyphenyl)propionic acid (m -HPPA) excretors. Evidence exists for the role of intestinal microflora in the excretion of aromatic phenolic compounds including HA and m -HPPA. 2. We sought to investigate whether intestinal microflora contribute to the difference in excretion. Urinary HA and m -HPPA levels were monitored to characterize excretion over time. The effect of intestinal microflora on the 1 H-NMR spectrum was also investigated using antibiotics to sterilize the intestine. Finally, the levels of m -HPPA and phenylpropionic acid (a precursor for HA) were analysed in the caecum and colon (entire tissue, including contents). 3. Characterization confirmed the presence of HA and m -HPPA excretors; enquiries revealed that the rats were obtained from two floors within a barriered breeding unit. Housing the rats from the two floors together for 21 days resulted in comparable levels of HA and m -HPPA excretion demonstrating that the profiles are not stable. 4. Following antibiotic treatment, HA and m -HPPA excretion decreased, indicating that intestinal microflora contribute to the excretion of these compounds. Finally, m -HPPA levels were higher in the colon of rats that excreted m -HPPA whilst PPA was increased in the caecum and colon of rats that excreted HA. 5. These results demonstrate that the observed difference in HA/ m -HPPA excretion is due to differences in the intestinal microflora.     

Nuclear magnetic resonance spectroscopy and genetic disorders

Nuclear magnetic resonance spectroscopy has been exploited to study the metabolic characteristics (phenotype) of genetic disorders by taking advantage of some unique characteristics of the technique. The first application, metabolic profiling for diagnosis and therapeutic monitoring in vitro, demonstrates the exceptional diversity of metabolites detected by NMR, and has resulted in new interest in significant metabolites largely ignored previously because other techniques do not detect them, e.g. betaine and creatine. Moreover, previously 'unknown' genetic disorders have been detected and characterised The same NMR technique can be effectively exploited for metabolic profiling of mutation models in yeast and mice, leading to a prominent role in the development of large scale metabolomic profiling to link genomic information with phenotype. The second application, magnetic resonance spectroscopy (MRS), exploits the unique possibility of studying human metabolism in vivo, which permits intracellular rather than extracellular metabolic profiling. When it is possible to detect the precise diagnostic metabolites in vivo, investigators have been able to link clinical status with cellular biochemistry, sometimes questioning the clinical value of extracellular (plasma) metabolite measurements. Thus, claims have been made that brain phenylalanine concentrations match more closely the clinical status of patients with phenylketonuria. These studies in vivo have also led to new diagnoses e.g. the disorders of creatine synthesis and transport, highlighting a new category of brain syndromes. Future applications of NMR are cautiously considered as they are critically dependent on continued improvement in resolution and sensitivity in turn generated by developments in magnet design and higher fields.     

氢质子磁共振波谱在一氧化碳中毒迟发性脑病诊断中的应用

目的探讨氢质子磁共振波谱（1H—MRS）各参数峰下面积在一氧化碳中毒后迟发性脑病的诊断价值。方法将研究对象分为两组,即临床拟诊的一氧化碳中毒迟发性脑病（DNS）组38例,健康对照组18例,对研究对象分别进行常规核磁共振成像（MRI）和激励回波采集（STEAM）检查,测量各感兴趣区化合物的峰下面积。结果获取的患者波谱数据显示N-乙酰天门冬氨酸（NAA）（881±76）,胆碱（Cho）（2352±86）,B、1谷氨酸类化合物（β、γGlx）（3024±187）,与对照组比较B、7Glx及Cho升高,但NAA降低,DNS组与对照组NAA、Cho、β、γGlx有显著差异（P〈0．05）;同时发现在0．9—1．40ppm间Lip峰值升高,峰下面积增加。结论。H-MRS的测定可能会在一定程度上协助急性一氧化碳中毒后迟发性脑病的诊断。     

Carbon-13 magnetic resonance spectroscopy of drugs II: antihistamines.

The natural abundance carbon-13 magnetic resonance spectra of a series of antihistamines (pheniramine, chlorpheniramine, methapyrilene, tripelennamine, pyrilamine, and thonzylamine) were detemined using the pulse Fourier transform technique. The chemical shifts were assigned with the aid of long-range carbon-13-hydrogen coupling constants.     

An in vivo animal model to study chronic adriamycin cardiotoxicity: a P-31 nuclear magnetic resonance spectroscopy investigation

The mechanism responsible for adriamycin induced cardiotoxicity is unknown. We have developed an in vivo rabbit model for use with P-31 nuclear magnetic resonance spectroscopy which allows serial investigations of the drug's effects on myocardial metabolism. Eleven animals were studied over a 10 week period and changes in intracellular pH and phosphate metabolites were observed. The magnitude of changes in pH and inorganic phosphate were the best indicators of the severity of the cardiomyopathy. The results are consistent with an adriamycin induced degeneration of myofibrils rather than a severe metabolic impairment.     

Shortened onset of action of antidepressants in major depression using acetylsalicylic acid augmentation: a pilot open-label study

Based on our preclinical data showing a potential accelerating effect of acetylsalicylic acid (ASA) in combination with fluoxetine in an animal model of depression, we examined the effect of ASA augmentation therapy on selective reuptake inhibitors (SSRI) in major depressed non-responder patients. Twenty-four non-responder patients having received at least 4 weeks of an adequate SSRI treatment were included in a pilot open-label study. Participants were treated openly during 4 weeks with 160 mg/day ASA in addition to their current antidepressant treatment. The combination SSRI-ASA was associated with a response rate of 52.4%. Remission was achieved in 43% of the total sample and 82% of the responder sample. In the responder group, a significant improvement was observed within week 1 (mean Hamilton Depression Rating Scale-21 items at day 0=29.3+/-4.5, at day 7=14.0+/-4.1; P<0.0001) and remained sustained until day 28. Despite limitations due to the open nature of this study, our preliminary results confirm our preclinical findings and are in favour of an accelerating effect of ASA in combination with SSRIs in the treatment of major depression. Potential physiological and biochemical mechanisms may involve an anti-inflammatory and/or neurotrophic effect.