Striatal neurometabolite levels in patients with schizophrenia undergoing long-term antipsychotic treatment: A proton magnetic resonance spectroscopy and reliability study.

Previous proton magnetic resonance spectroscopy (1H-MRS) studies have reported disrupted levels of various neurometabolites in patients with schizophrenia. An area of particular interest within this patient population is the striatum, which is highly implicated in the pathophysiology of schizophrenia. The present study examined neurometabolite levels in the striatum of 12 patients with schizophrenia receiving antipsychotic treatment for at least 1 year and 11 healthy controls using 3-Tesla 1H-MRS (PRESS, TE = 35 ms). Glutamate, glutamate+glutamine (Glx), myo-inositol, choline, N-acetylaspartate, and creatine levels were estimated using LCModel, and corrected for fraction of cerebrospinal fluid in the 1H-MRS voxel. Striatal neurometabolite levels were compared between groups. Multiple study visits permitted a reliability assessment for neurometabolite levels (days between paired 1H-MRS acquisitions: average = 90.33; range = 7-306). Striatal neurometabolite levels did not differ between groups. Within the whole sample, intraclass correlation coefficients for glutamate, Glx, myo-inositol, choline, and N-acetylaspartate were fair to excellent (0.576-0.847). The similarity in striatal neurometabolite levels between groups implies a marked difference from the antipsychotic-naïve first-episode state, especially in terms of glutamatergic neurometabolites, and might provide insight regarding illness progression and the influence of antipsychotic medication.

1H-NMR-based metabolomic analysis of cerebrospinal fluid from adult bilateral moyamoya disease: comparison with unilateral moyamoya disease and atherosclerotic stenosis.

Although metabolomics has been increasingly used to observe metabolic pattern and disease-specific metabolic markers, metabolite profiling for moyamoya disease (MMD) has not yet been done in adults. This study investigated cerebrospinal fluid (CSF) metabolites specific to bilateral MMD (B-MMD) and compared them to those of unilateral MMD (U-MMD) or atherosclerotic stenosis with hydrogen-1 nuclear magnetic resonance spectroscopy to identify metabolic biomarkers associated with MMD in adults.CSF samples of B-MMD (n = 29), U-MMD (n = 11), and atherosclerotic cerebrovascular disease (ACVD) (n = 8) were recruited. Principal component analysis, partial least square discriminant analysis, and orthogonal projections to latent structure discriminant analysis (OPLS-DA) were done for the comparisons. Diagnostic performance was acquired by prediction of 1 left-out sample from the distinction model constructed with the rest of the samples.B-MMD showed an increase in glutamine (P < 0.001) and taurine (P = 0.004), and a decrease in glucose (P < 0.001), citrate (P = 0.002), and myo-inositol (P = 0.006) than those in ACVD. U-MMD showed a higher level of glutamine (P = 0.005) and taurine (P = 0.034), and a lower level of glutamate (P < 0.004) than those in ACVD. No difference at the metabolite level was observed between B-MMD and U-MMD. Cross-validation with the OPLS-DA model showed a high accuracy for the prediction of MMD.The results of the study suggest that a metabolomics approach may be helpful in confirming MMD and providing a better understanding of MMD pathogenesis. Elevated glutamine in the CSF may be associated with MMD pathogenesis, which was different from ACVD.

An NMR metabolomics approach for the diagnosis of leptomeningeal carcinomatosis in lung adenocarcinoma cancer patients.

Leptomeningeal carcinomatosis (LC) is a metastatic cancer invading the central nervous system (CNS). We previously reported a metabolomic diagnostic approach as tested on an animal model and compared with current modalities. Here, we provide a proof of concept by applying it to human LC originating from lung cancer, the most common cause of CNS metastasis. Cerebrospinal fluid from LC (n = 26) and normal groups (n = 41) were obtained, and the diagnosis was established with clinical signs, cytology, MRI and biochemical tests. The cytology on the CSF, the current gold standard, exhibited 69% sensitivity (~100% specificity) from the first round of CSF tapping. In comparison, the nuclear magnetic resonance spectra on the CSF showed a clear difference in the metabolic profile between the LC and normal groups. Multivariate analysis and cross-validation yielded the diagnostic sensitivity of 92%, the specificity of 96% and the area under the curve (AUC) of 0.991. Further spectral and statistical analysis identified myo-inositol (p < 5 × 10(-14)), creatine (p < 7 × 10(-8)), lactate (p < 9 × 10(-4)), alanine (p < 7.9 × 10(-3)) and citrate (p < 3 × 10(-4)) as the most contributory metabolites, whose combination exhibited an receiver-operating characteristic diagnostic AUC of 0.996. In addition, the metabolic profile could be correlated with the grading of radiological leptomeningeal enhancement (R(2) = 0.3881 and p = 6.66 × 10(-4)), suggesting its potential utility in grading LC. Overall, we propose that the metabolomic approach might augment current diagnostic modalities for LC, the accurate diagnosis of which remains a challenge.

Metabolic alterations in medication-free patients with bipolar disorder: a 3T CSF-corrected magnetic resonance spectroscopic imaging study.

The objective of this study was to determine whether cerebrospinal fluid(CSF)-corrected concentrations of N-acetylaspartate are lower in several brain regions of drug- and medication-free subjects with bipolar disorder as compared with matched healthy controls. Bipolar subjects (n=21) and age- and sex-matched healthy control (n=21) were studied using proton magnetic resonance spectroscopic imaging on a 3T magnetic resonance (MR) scanner. Spectra were quantified using the LCModel, and metabolite values were CSF-corrected to yield metabolite concentrations. Fourteen regions of interest and five metabolite concentrations in each subject were selected for statistical analysis. We found that bipolar subjects had significantly decreased N-acetylaspartate concentrations in both caudate heads and the left lentiform nucleus. Choline and creatine in the head of the right caudate were also significantly decreased in bipolar subjects. Significantly increased myo-inositol was found in the left caudate head in bipolar subjects. Bipolar subjects showed significantly decreased glutamate/glutamine concentrations in the frontal white matter bilaterally and in the right lentiform nucleus. No differences were found for other metabolites examined. These preliminary findings suggest decreased neuronal density or viability in the basal ganglia and neurometabolic abnormalities in the frontal lobes of subjects with bipolar disorder.

Properties of scyllo-inositol as a therapeutic treatment of AD-like pathology.

Inositol is a simple polyol with eight naturally occurring stereoisomers. myo-Inositol, D-chiro- and epi-inositol have been examined as potential therapeutic agents for various diseases, with favorable results, but treatment with scyllo-inositol has not been previously investigated. Our laboratory has shown that scyllo-inositol inhibits cognitive deficits in TgCRND8 mice and significantly ameliorates disease pathology, suggesting it might be effective in treating Alzheimer's disease (AD). In this paper, we show that scyllo-inositol has a sustained ability to treat animals at advanced stages of AD-like pathology. Significant decreases in insoluble Abeta40, Abeta42, and plaque accumulation were observed in the brains of treated versus untreated TgCRND8 mice. The growth of plaques of all sizes was inhibited by scyllo-inositol administration. To demonstrate that the scyllo-inositol effects were within the CNS, gas chromatography/mass spectrometry was used to examine myo- and scyllo-inositol concentrations after oral administration. Further, we examined how closely scyllo- and myo-inositol are inter-regulated in the CNS and whether scyllo-inositol, if elevated within the CNS, would incorporate into phosphatidylinositol lipids. Cerebral spinal fluid levels of scyllo-inositol increased after scyllo-inositol treatment but not myo-inositol treatment. scyllo-Inositol treatment also caused increased levels of scyllo-inositol in the brain. We further show that scyllo-inositol, even at elevated levels, does not incorporate into the phosphatidylinositol family of lipids. These combined results demonstrate that scyllo-inositol accumulates within the CNS up to tenfold endogenous levels and does not interfere with phosphatidylinositol lipid production.

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.

Metabolic changes in the cerebrospinal fluid of patients with lumbar disc herniation or spinal stenosis.

Metabolite levels in cerebrospinal fluid from patients with lower back pain and/or sciatica caused by disc herniation or spinal stenosis were compared with levels in pain-free controls using proton magnetic resonance spectroscopy. Significant differences for several metabolites were found in patients with pain compared with controls. Most changes were found in the group with disc herniation, including reductions in glucose, alanine, and lactate, suggesting increased aerobic metabolism in this group. There was a significant reduction in the level of glucose in the group with spinal stenosis irrespective of whether the patients were compared with the whole control group (age-weighted) or with age-matched controls. Additionally, inositol and creatinine were reduced in patients with disc herniation. Inositol was also significantly reduced in the spinal stenosis group when age matched to controls. Insofar as the levels of pain recorded by the patients with lumbar pathology were similar in the two groups, it seems more likely that the reductions in metabolite levels recorded in the group with disc herniations are related to disc pathology rather than the perception of pain. However, the possibility that pain perception contributes to the metabolic changes cannot be excluded.

1H-NMR spectroscopy of cerebrospinal fluid of fetal sheep during hypoxia-induced acidemia and recovery.

The purpose of the study was to investigate the sequence of processes occurring during and after hypoxia-induced acidemia. We used proton nuclear magnetic resonance spectroscopy, which provides an overview of metabolites in cerebrospinal fluid (CSF), reflecting neuronal metabolism and damage. The pathophysiological condition of acute fetal asphyxia was mimicked by reducing maternal uterine blood flow in 14 unanesthetized pregnant ewes. CSF metabolites were measured during hypoxia-induced acidemia, and during the following recovery period, including the periods at 24 and 48 h after the hypoxic insult. Maximum values of the following CSF metabolites were reached during severe hypoxia (pH

Stability of CSF metabolites measured by proton NMR.

Analysis of cerebrospinal fluid (CSF) metabolites can provide data regarding CNS involvement in neurologic and psychiatric illness. However, there is lack of research into the effect of processing and storage of CSF specimens on the levels of metabolites analyzed. CSF specimens from 10 depressed patients were analyzed by proton NMR before and after 72 hours exposure to room temperature. No effect of exposure was found on myoinositol, glucose, acetate, and alanine CSF levels and there was a substantial decrease of citrate (>50%) and increase in lactate, glutamine, creatine, and creatinine levels.

Glutamine, myo-inositol, and organic brain osmolytes after portocaval anastomosis in the rat: implications for ammonia-induced brain edema.

Brain myo-inositol, an organic osmolyte, is decreased in cirrhotic patients with hepatic encephalopathy but appears unchanged in fulminant hepatic failure. An osmoregulatory response to the increase in brain glutamine may explain the decrease in brain myo-inositol; if this is the case, organic osmolytes may account for differences in the development of brain edema seen in acute or chronic liver failure. The response of myo-inositol and nine other organic osmolytes to the increase in brain glutamine at different time intervals after portacaval anastomosis (PCA) in the rat was studied. Organic osmolytes were measured in brain tissue and cerebrospinal fluid. Water in cerebral cortex was measured after ammonia infusion with the gravimetric method. Six weeks after PCA, despite an increase in brain glutamine (PCA, 16.4 +/- 2 mmol.kg wt-1.kg wt-1; sham, 5 +/- 1 mmol.L-1.kg wt-1), the content of total organic osmolytes did not increase (PCA, 44.1 +/- 3; sham, 43 +/- 4) because of a decrease of other osmolytes (myo-inositol, 54%; urea, 39%; taurine, 33%; and glutamate, 8%). Brain myo-inositol was lower at 3 weeks (3.4 +/- 0.5 kg wt-1) than at 1 day after PCA (4.7 +/- 0.5 kg wt-1). An ammonia infusion resulted in brain edema at both time points. In conclusion, the reduction in brain myo-inositol in PCA rats is accompanied by the decrease of other organic osmolytes, supporting the view that changes in myo-inositol reflect an osmoregulatory response. The decrease in brain myo-inositol is more marked as time elapses after PCA. In a model in which short-term and large doses of ammonia were infused, the decrease in brain myo-inositol did not prevent the development of brain swelling. Understanding brain osmoregulatory mechanisms may provide new insights into hepatic encephalopathy and brain edema in fulminant hepatic failure.

Cerebrospinal fluid and plasma distribution of myo-inositol and other polyols in Alzheimer disease.

Previous studies suggest the presence of increased concentrations of cerebral myo-inositol in Alzheimer disease (AD). To characterize this abnormality further, we quantified myo-inositol and several other polyols in cerebrospinal fluid (CSF) and plasma from 10 AD subjects and 10 healthy age-matched controls by using a gas chromatographic-mass spectrometric technique. The mean CSF concentration and CSF/plasma concentration ratio of myo-inositol in AD were not significantly different from those determined in control subjects. Also, concentration profiles of other polyols were not significantly altered in AD. CSF and plasma myo-inositol concentrations were correlated in control subjects but not in AD subjects. However, a significant correlation between CSF and plasma 1,5-anhydrosorbitol (a polyol internal control) concentrations observed in control subjects was retained in AD subjects.

CSF inositol does not predict antidepressant response to inositol. Short communication.

CSF inositol was reported to be reduced in depression and inositol has been reported to be effective in treatment of depression. We studied CSF inositol in 18 drug-free depressed patients and 36 normal controls; the depressed patients then participated in an open trial of 18 gm daily inositol treatment for 4 weeks. There was no difference in pre-treatment CSF inositol between depressed patients and controls. CSF inositol levels did not predict response on the Hamilton Depression Scale to 4 weeks of inositol treatment.

Polyol profiles in Down syndrome. myo-Inositol, specifically, is elevated in the cerebrospinal fluid.

Polyols are reduction products of aldoses and ketoses; their concentrations in tissues can reflect carbohydrate metabolism. Several polyol species were quantitated in cerebrospinal fluid (CSF) and plasma from 10 Down Syndrome (trisomy 21) subjects between the ages of 22 and 63 years (3 of whom were demented) and from 10 healthy age-matched controls, using a gas chromatographic/mass spectrometric technique. The mean CSF concentration and the mean CSF/plasma concentration ratio of myo-inositol were significantly elevated in Down syndrome compared with controls, but were not correlated with the presence of dementia in the Down subjects. Plasma myo-inositol was not significantly altered in these subjects. No significant difference between Down syndrome and controls was found for CSF concentrations of mannitol, sorbitol, galactitol, ribitol, arabitol, or 1,5-anhydrosorbitol, but plasma mannitol, ribitol and arabitol were elevated in Down syndrome. The present observation provides new impetus for studying synthesis and transport of myo-inositol as well as phosphatidylinositol cycle in trisomy 21 disorder.

CSF inositol in schizophrenia and high-dose inositol treatment of schizophrenia.

Inositol is a key metabolite in the phosphatidylinositol cycle, which is a second messenger system for serotonin-2 receptors that have been implicated in the pathophysiology of schizophrenia. Cerebrospinal fluid inositol levels were measured in 20 schizophrenic patients and 19 age- and sex-matched controls and no difference was found. However, the patients were all neuroleptic-treated. A controlled double-blind crossover trial of 12 g daily of inositol for a month in 12 anergic schizophrenic patients, twice the dose given before in schizophrenia, did not show any beneficial effects. However, the number of patients studied was small and the length of time of inositol administration may not have been sufficient.

Assay of myo-inositol in cerebrospinal fluid and plasma by chemical ionization mass spectrometry of the hexaacetate derivative.

The paper describes a capillary gas chromatographic/mass spectrometric technique to quantitate myo-inositol in cerebrospinal fluid (CSF) and plasma. A highly abundant fragment ion, m/z 373, for the hexaacetate derivative of myo-inositol was generated by chemical ionization (CI). This ion and the analogous ion of hexadeuterated myo-inositol (the internal standard), m/z 379, were both monitored in the assay. CI was performed with acetonitrile vapor in an ion trap mass spectrometer. Microliter quantities of CSF or plasma were mixed with the internal standard, dried and acetylated. After a post-derivatization clean-up, samples were analyzed on a capillary gas chromatograph interfaced with a Finnigan ion trap. Standard curves constructed for both CSF and plasma were linear and reproducible. Absence of matrix effects and good precision in the results indicate the suitability of the technique for critical assays. Results from the determination of myo-inositol in the CSF and plasma of healthy subjects and those with neurological deficits are reported.

Inositol treatment raises CSF inositol levels.

Inositol is a key precursor for synthesis of phosphatidylinositol in a major second messenger signalling system. It is biologically active in syndromes such as respiratory distress syndrome but has been thought to be excluded from CNS by the blood-brain barrier. Oral inositol treatment of 8 patients is shown to significantly increase CSF inositol by almost 70%, suggesting possible CNS therapeutic applications of this compound and possible CNS side-effects of systemic therapy.

The role of myo-inositol in multiple sclerosis.

Myo-inositol was given orally to nine multiple sclerosis patients and nine healthy control subjects. Pattern reversal evoked potential testing was used to assess its effect. The principal positive wave increased in amplitude, duration and area in a dose-dependent manner in the multiple sclerosis group compared with controls. Cerebrospinal fluid concentrations of myo-inositol in multiple sclerosis and controls were similar. The significance of these observations is discussed in relation to recent discoveries in inositol phospholipid function.

Gas chromatographic-mass spectrometric determination of myo-inositol in human cerebrospinal fluid.

The concentration of free myo-inositol in CSF was determined with a gas chromatographic-mass spectrometric method using deuterated myo-inositol as an internal standard after conversion to the hexa-O-acetyl derivative with acetic anhydride and pyridine. Twenty microliters of CSF is sufficient for the analysis which has a coefficient of variation of 9%. Identical analytical results were obtained on two different mass numbers. Schizophrenic patients were compared with healthy control persons. In addition, patients with rheumatoid arthritis or with neurological illnesses were studied. No consistent differences related to the illness could be found. The mean concentration of myo-inositol was about 25 micrograms/ml. Treatment of schizophrenic patients with chlorpromazine or sulpiride had no significant effect on the concentration of myo-inositol in CSF.

[Inositol in the cerebrospinal fluid, plasma and erythrocytes in spinal pain syndromes]. / Inozytol w plynie mózgowo-rdzeniowym, osoczu i krwinkach czerwonych w zespolach bólowych kregoslupa.

The studies, performed on 40 patients with brachialgia and ischialgia syndromes, showed higher CSF inositol concentrations in comparison with healthy subjects. The highest rise was observed particularly in patients in the initial stage of disease, while the rise was lower in more severe forms of the disease and in cases with root compression confirmed by radiculography. Blood plasma and erythrocyte concentrations of inositol and phosphatidylinositol were within normal range, although they significantly differed in various brachialgia and ischialgia syndromes.