Effects of acetyl-L-carnitine and myo-inositol on high-energy phosphate and membrane phospholipid metabolism in zebra fish: a 31P-NMR-spectroscopy study.

Acetyl-L-carnitine (ALCAR) and myo-inositol are reported to enhance motor activity in animal models; modulate membrane phospholipid metabolism (ALCAR and myo-inositol) and high-energy phosphate metabolism (ALCAR) back to normal; and be effective treatments of major depression in humans. Fish in general and zebra fish in particular present unique animal models for the in vivo study of high-energy phosphate and membrane phospholipid metabolism by noninvasive in vivo 31P NMR. This 31P NMR study of free-swimming zebra fish showed that both ALCAR and myo-inositol decreased levels of phosphodiesters and inorganic orthophosphate and increased levels of PCr in the fish. These findings demonstrate both ALCAR and myo-inositol modulate membrane phospholipid and high-energy phosphate metabolism in free-swimming zebra fish.

Prefrontal membrane phospholipid metabolism of child and adolescent offspring at risk for schizophrenia or schizoaffective disorder: an in vivo 31P MRS study.

In vivo (31)P magnetic resonance spectroscopy ((31)P MRS) studies have shown abnormal membrane phospholipid metabolism in the prefrontal cortex (PF) in the early course of schizophrenia. It is unclear, however, whether these alterations also represent premorbid risk indicators in schizophrenia. In this paper, we report in vivo (31)P MRS data on children and adolescents at high risk (HR) for schizophrenia. In vivo (31)P MRS studies of the PF were conducted on 16 nonpsychotic HR offspring of parents with schizophrenia or schizoaffective disorder, and 37 age-matched healthy comparison (HC) subjects. While 11 of the HR subjects had evidence of Axis I psychopathology (HR-P), five HR subjects had none (HR-NP). We quantified the freely mobile phosphomonoester (PME) and phosphodiester (PDE) levels reflecting membrane phospholipid precursors and breakdown products, respectively, and the relatively broad signal underlying PDE and PME peaks, comprised of less mobile molecules with PDE and PME moieties (eg, synaptic vesicles and phosphorylated proteins). Compared to HC subjects, HR subjects had reductions in freely mobile PME; the differences were accounted for mainly by the HR-P subjects. Additionally, HR-P subjects showed increases in the broad signal underlying the PME and PDE peaks in the PF. To conclude, these data demonstrate new evidence for decreased synthesis of membrane phospholipids and possibly altered content or the molecular environment of synaptic vesicles and/or phosphoproteins in the PF of young offspring at risk for schizophrenia. Follow-up studies are needed to examine the predictive value of these measures for future emergence of schizophrenia in at-risk individuals.

Abnormalities of the corpus callosum in first episode, treatment naive schizophrenia.

BACKGROUND: Structural alterations in the association cortices as well as in the corpus callosum (CC) have been described in schizophrenia, and have been considered to reflect developmental abnormalities. Areas of primary and association cortices have been topographically mapped in the CC. OBJECTIVE: To investigate whether, in schizophrenia, there are alterations in CC subdivisions that connect association, but not primary, cortices, and also to see if the normative, developmentally mediated increase in CC size with age is absent in this disorder. METHODS: The midsagittal magnetic resonance imaging scans of 31 first episode, neuroleptic naive, schizophrenic patients, 12 non-schizophrenic, psychotic patients, and 31 healthy controls were compared. The total area of CC as well as that of anterior, middle and posterior genu, body, isthmus, and anterior, middle, and posterior splenii were measured. RESULTS: Patients with schizophrenia as a group had a smaller CC, anterior genu, anterior body, isthmus, and anterior splenium than normal controls. Furthermore, the age related increase in CC size seen in normal subjects was absent in the patients. CONCLUSIONS: The observed reductions in size in selected regions of CC suggest a reduction in axonal connections between the heteromodal association cortices, which typically involve small diameter fibres. Furthermore, the absence of an age related increase in CC size in patients with schizophrenia suggests a neurodevelopmental abnormality that may extend into adolescence and early adulthood.

Effects of chronic lithium administration on rat brain phosphatidylinositol cycle constituents, membrane phospholipids and amino acids.

OBJECTIVE: There is evidence linking affective disorders and their treatment to alterations in membrane phospholipid metabolism, the phosphatidylinositol (PtdIns) second messenger cycle and brain excitatory and inhibitory amino acids. This study examines lithium effects on rat brain metabolites associated with the above systems and their reversal by myo-inositol. METHODS: Thirty rats were treated for 14 days with i.p. lithium, saline or lithium plus myo-inositol. 1H, 31P and 7Li NMR were used to measure brain metabolites. RESULTS: Lithium, administered alone or with myo-inositol, resulted in brain lithium concentrations of approximately 0.6 microM/gram brain tissue. Brain myo-inositol was unchanged when lithium was co-administered with myo-inositol. Lithium increased brain inositol-1-phosphate (I1P) by 98% compared with saline and this effect was not attenuated by the addition of myo-inositol. Lithium treatment decreased phosphatidylserine (PtdSer) and PtdIns by 3% and 8%, respectively. Lithium also decreased taurine levels by 8% and increased aspartate levels by 9%. The above effects of lithium on PtdSer, PtdIns and taurine were attenuated or abolished by the co-administration of myo-inositol. CONCLUSIONS: Lithium alters levels of key membrane phospholipids and appears to affect the balance between inhibitory and excitatory amino acids in rat brain. Co-administration of myo-inositol attenuates some of these lithium effects on brain metabolites.

Brain membrane phospholipid alterations in Alzheimer's disease.

Studies have demonstrated alterations in brain membrane phospholipid metabolite levels in Alzheimer's disease (AD). The changes in phospholipid metabolite levels correlate with neuropathological hallmarks of the disease and measures of cognitive decline. This 31P nuclear magnetic resonance (NMR) study of Folch extracts of autopsy material reveals significant reductions in AD brain levels of phosphatidylethanolamine (PtdEtn) and phosphatidylinositol (PtdIns), and elevations in sphingomyelin (SPH) and the plasmalogen derivative of PtdEtn. In the superior temporal gyrus, there were additional reductions in the levels of diphosphatidylglycerol (DPG) and phosphatidic acid (PtdA). The findings are present in 3/3 as well as 3/4 and 4/4 apolipoprotein E (apoE) genotypes. The AD findings do not appear to reflect non-specific neurodegeneration or the presence of gliosis. The present findings could possibly contribute to an abnormal membrane repair in AD brains which ultimately results in synaptic loss and the aggregation of A beta peptide.

Brain metabolic effects of acute nicotine.

(-)Nicotine acetylcholine receptors are located on both nerve cell bodies and synaptic terminals, are permeable to calcium, and function perhaps predominantly by facilitating the release of neurotransmitters and neuropeptides. The behavioral rewards from (-)nicotine and perhaps addiction appear to be related to dopamine release. 31P NMR analysis reveals subcutaneously administered (-)nicotine produces acute alterations in brain membrane phospholipid and high-energy phosphate metabolism of Fischer 344 rats. These metabolic responses to (-)nicotine could contribute to nicotine's behavioral effects.

Chronic myo-inositol increases rat brain phosphatidylethanolamine plasmalogen.

BACKGROUND: Oral myo-inositol (12--18 g/day) has shown beneficial effect in placebo-controlled studies of major depression, panic disorder, and obsessive compulsive disorder, and preliminary data suggest it also may be effective in bipolar depression. Evidence linking antidepressant activity to membrane phospholipid alterations suggested the examination of acute and chronic myo-inositol effects on rat brain membrane phospholipid metabolism. METHODS: With both (31)P nuclear magnetic resonance (NMR) and quantitative high-performance thin-layer chromatography (HPTLC; hydrolysis) methods, rat brain phospholipid levels were measured after acute (n = 20, each group) and chronic myo-inositol administration (n = 10, each group). With (31)P NMR, we measured myo-inositol rat brain levels after acute and chronic myo-inositol administration. RESULTS: Brain myo-inositol increased by 17% after acute myo-inositol administration and by 5% after chronic administration, as compared with the control groups. Chronic myo-inositol administration increased brain phosphatidylethanolamine (PtdEtn) plasmalogen by 10% and decreased brain PtdEtn by 5%, thus increasing the ratio PtdEtn plasmalogen (PtdEtn-Plas)/PtdEtn by 15%. Phosphatidylethanolamine plasmalogen levels quantified by (31)P NMR and HPTLC were highly correlated. The validity and reliability of the (31)P NMR method for phospholipid analysis were demonstrated with phospholipid standards. CONCLUSIONS: The observed alteration in the PtdEtn-Plas/PtdEtn ratio could provide insights into the therapeutic effect of myo-inositol in affective disorders.

Postprocessing method to segregate and quantify the broad components underlying the phosphodiester spectral region of in vivo (31)P brain spectra.

In a typical, in vivo (31)P brain spectrum, the phosphomonoester (PME) and phosphodiester (PDE) spectral region not only contains signals from freely mobile PMEs and PDEs (which are anabolic and catabolic products of membrane phospholipids) but also signals of broader underlying lineshapes from less-mobile molecules. In general, either the PME and PDE resonances are quantified as a combined value of freely mobile metabolites plus less-mobile molecules or the broader underlying signal is reduced/eliminated prior to or post data collection. In this study, a postprocessing method that segregates and quantifies the individual contributions of the freely mobile metabolites and the less-mobile molecules is introduced. To demonstrate the precision and accuracy of the method, simulated data and in vivo (31)P brain spectroscopy data of healthy individuals were quantified. The ability to segregate and quantify these various PME and PDE contributions provides additional spectral information and improves the accuracy of the interpretation of (31)P spectroscopy results. Magn Reson Med 45:390-396, 2001.

Acetyl-L-carnitine physical-chemical, metabolic, and therapeutic properties: relevance for its mode of action in Alzheimer's disease and geriatric depression.

Acetyl-L-carnitine (ALCAR) contains carnitine and acetyl moieties, both of which have neurobiological properties. Carnitine is important in the beta-oxidation of fatty acids and the acetyl moiety can be used to maintain acetyl-CoA levels. Other reported neurobiological effects of ALCAR include modulation of: (1) brain energy and phospholipid metabolism; (2) cellular macromolecules, including neurotrophic factors and neurohormones; (3) synaptic morphology; and (4) synaptic transmission of multiple neurotransmitters. Potential molecular mechanisms of ALCAR activity include: (1) acetylation of -NH2 and -OH functional groups in amino acids and N terminal amino acids in peptides and proteins resulting in modification of their structure, dynamics, function and turnover; and (2) acting as a molecular chaperone to larger molecules resulting in a change in the structure, molecular dynamics, and function of the larger molecule. ALCAR is reported in double-blind controlled studies to have beneficial effects in major depressive disorders and Alzheimer's disease (AD), both of which are highly prevalent in the geriatric population.

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.

Magnetic resonance spectroscopy in schizophrenia: methodological issues and findings--part I.

Our knowledge of the biological basis of schizophrenia has significantly increased with the contribution of in vivo proton and phosphorus magnetic resonance spectroscopy (MRS), a noninvasive tool that can assess the biochemistry from a localized region in the human body. Studies thus far suggest altered membrane phospholipid metabolism at the early stage of illness and reduced N-acetylaspartate, a measure of neuronal volume/viability in chronic schizophrenia. Inconsistencies remain in the literature, in part due to the complexities in the MRS methodology. These complexities of in vivo spectroscopy make it important to understand the issues surrounding the design of spectroscopy protocols to best address hypotheses of interest. This review addresses these issues, including 1) understanding biochemistry and the physiologic significance of metabolites; 2) the influence of acquisition parameters combined with spin-spin and spin-lattice relaxation effects on the MRS signal; 3) the composition of spectral peaks and the degree of overlapping peaks, including the broader underlying peaks; 4) factors affecting the signal-to-noise ratio; 5) the various types of localization schemes; and 6) the objectives to produce accurate and reproducible quantification results. The ability to fully exploit the potentials of in vivo spectroscopy should lead to a protocol best optimized to address the hypotheses of interest.

Magnetic resonance spectroscopy in schizophrenia: methodological issues and findings--part II.

Magnetic resonance spectroscopy allows investigation of in vivo neurochemical pathology of schizophrenia. "First generation" studies, focusing on phosphorus and proton magnetic resonance spectroscopy, have suggested alterations in membrane phospholipid metabolism and reductions in N-acetyl aspartate in the frontal and temporal lobes. Some discrepancies remain in the literature, perhaps related to the variations in medication status and phase of illness in the patients examined, as well as in magnetic resonance spectroscopy methodology; the pathophysiologic significance of the findings also remains unclear. Technologic advances in magnetic resonance spectroscopy in recent years have expanded the potential to measure several other metabolites of interest such as the neurotransmitters glutamate and gamma-aminobutyric acid and macromolecules such as membrane phospholipids and synaptic proteins. Issues of sensitivity, specificity, measurement reliability, and functional significance of the magnetic resonance spectroscopy findings need to be further clarified. The noninvasive nature of magnetic resonance spectroscopy allows longitudinal studies of schizophrenia both in its different phases and among individuals at genetic risk for this illness. Future studies also need to address confounds of prior treatment and illness chronicity, take advantage of current pathophysiologic models of schizophrenia, and be hypothesis driven.

Increased cerebrospinal fluid glutamine levels in depressed patients.

BACKGROUND: There is increasing evidence for an association between alterations of brain glutamatergic neurotransmission and the pathophysiology of affective disorders. METHODS: We studied the association between cerebrospinal fluid (CSF) metabolites, including glutamine, in unipolar and bipolar depressed patients versus control subjects using a proton magnetic resonance spectroscopy technique. Cerebrospinal fluid samples were obtained from 18 hospitalized patients with acute unmedicated severe depression without medical problems and compared with those of 22 control subjects. RESULTS: Compared with the control group, the depressed patient group had significantly higher CSF glutamine concentrations, which correlated positively with CSF magnesium levels. CONCLUSIONS: These findings suggest an abnormality of the brain glial-neuronal glutamine/glutamate cycle associated with N-methyl-D-aspartate receptor systems in patients with depression.

Molecular insights into neurodevelopmental and neurodegenerative diseases.

Magnetic resonance spectroscopy (MRS) is a non-invasive physical technique that is routinely used to determine the quantity and structure of organic molecules in solution. Technical advances that have expanded the usefulness of this technique include: (1) high resolution MRS to identify and quantify individual molecules present in complex mixtures of tissue extracts; (2) in vivo MRS techniques to non-invasively monitor metabolites in humans; (3) structure determination of proteins of moderate size; and (4) improved structure characterization of solids and liquid crystals, such as the detection of phase changes in membranes. The focus of this review is on the first two technical advances mentioned above. The strengths of MRS as a research tool to investigate molecular alterations in disease states include ease of sample preparation, minimum sample manipulation, avoidance of the preparation of derivatives, and the ability to analyze an unfractionated sample. The strengths of MRS in the clinic are its ability to measure neuronal metabolite levels non-invasively in humans and its potential for disease diagnosis, monitoring disease progression, and assessing the efficacy of experimental therapies.

Landmark-based morphometric analysis of first-episode schizophrenia.

BACKGROUND: The goal of this investigation was to utilize landmark-based shape analysis and image averaging to determine the sites and extent of specific structural changes in first-episode schizophrenia. METHODS: Neuroanatomic structures identified on midsagittal magnetic resonance imaging (MRI) scans were compared between 20 patients with schizophrenia and 22 normal control subjects. The difference between averaged landmark configurations in the two groups was visualized as a shape deformation by a thin-plate spline and through averaged MRI images for both groups. RESULTS: A shape difference was found to be statistically significant; by inspection, it is contrast between differences in two closely abutting regions, involving primarily the posterior corpus callosum and upper brain stem--the "focus" is the relation between them. CONCLUSIONS: The findings are consistent with prior studies suggesting involvement in schizophrenia of the corpus callosum and the limbic structures contributing to the corpus callosum; the possibility of local pathology primarily involving the brain stem cannot be excluded. The methods of landmark-based shape analysis and image averaging utilized in this study can complement the "region-of-interest" method of investigating morphometric abnormalities by characterizing the spatial relationships among structural brain abnormalities in schizophrenia.

Chrysamine-G, a lipophilic analogue of Congo red, inhibits A beta-induced toxicity in PC12 cells.

Increasing evidence suggests that deposition of amyloid-beta (A beta) peptide leads to neurodegeneration in Alzheimer's disease. Congo red, a histologic dye that binds to amyloid has previously been shown to diminish the toxic effects of A beta in cell culture. Since Congo red is too highly charged to enter the brain in significant quantities, a lipophilic derivative, Chrysamine-G, was tested for the ability to attenuate A beta[25-35]-induced toxicity in PC12 cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Chrysamine-G showed a concentration-dependent inhibition of A beta[25-35]-induced toxicity. This protective effect became significant at 0.2 microM, a concentration very close to the Ki for Chrysamine-G binding to synthetic A beta (0.37 microM). A decarboxy derivative of Chrysamine-G, which does not bind to A beta, also did not protect against A beta-induced toxicity. The protective effects of Chrysamine-G may relate to its ability to bind directly to A beta and may involve other post-binding effects as well.

Superior temporal gyrus and the course of early schizophrenia: progressive, static, or reversible?

Accumulating evidence suggests alterations in brain structure, especially in the prefrontal and temporal cortex, in schizophrenia. Previous studies examining the progression of brain structural alterations in schizophrenia have led to conflicting results. Morphometric studies of the superior temporal gyrus (STG) volumes were conducted in a series of neuroleptic-naive first-episode schizophrenic patients, non-schizophrenic first-episode psychotic patients, and matched healthy controls. Three-dimensional MRI scans were carried out in these subjects before and after one year of treatment. Volume reductions were seen at baseline in the left superior temporal gyrus (adjusted for intracranial volume) in both of the patient groups. Pretreatment illness duration was inversely related to the volume of the left superior temporal gyrus; this relation was confined to males. One-year follow-up MRI investigations in a smaller subset of patients suggested that the STG volume reductions may be reversible. No significant changes were noted in the STG volumes in matched healthy controls who were also scanned at baseline as well as at one-year follow-up. These findings have implications for understanding the nature of the neuropathological processes in early schizophrenia, as well as the potential impact of early treatment.

Research and treatment strategies in first-episode psychoses. The Pittsburgh experience.

BACKGROUND: Studies of first-episode patients allow investigation of the biological basis of psychotic disorders without the potential confounds of prior treatment and illness chronicity. Prospective studies of this population can clarify the impact of illness course and treatment on neurobiology. METHOD: We summarise preliminary findings from our ongoing magnetic resonance imaging and spectroscopy studies of first-episode schizophrenia patients being conducted prospectively from index evaluations through a period of two years; during this period, patients were treated with either a conventional antipsychotic such as haloperidol, or the atypical risperidone. RESULTS: Baseline neurobiological evaluations in first-episode schizophrenia patients have revealed evidence for structural and functional brain abnormalities consistent with a neurodevelopmental model of this illness. Our preliminary data support the value of risperidone as an antipsychotic drug of first choice among patients with early schizophrenic illness. CONCLUSIONS: Focused studies of first-episode patients have the potential to unravel pathophysiology of schizophrenic illness. Such knowledge is critical for more effective early detection, intervention and even prevention of this enigmatic disorder.

Decreased caudate volume in neuroleptic-naive psychotic patients.

OBJECTIVE: Previous studies, mostly involving neuroleptic-treated patients, have suggested enlarged basal ganglia size in schizophrenia. The authors sought to examine basal ganglia volume in neuroleptic-naive psychotic patients. METHOD: Magnetic resonance imaging volumetric studies were conducted in newly diagnosed neuroleptic-naive schizophrenic and non-schizophrenic psychotic patients and in matched healthy comparison subjects. RESULTS: Both patient groups had bilaterally reduced caudate, but not putamen, volumes, compared to the healthy subjects, after adjustment for intracranial volume. CONCLUSIONS: Decreases in caudate volume in newly diagnosed psychotic patients may be related to the primary pathophysiology of these disorders; prior observations of increased caudate volume may reflect effects of neuroleptic treatment.

Chemical and physiologic brain imaging in schizophrenia.

Technologic advances in functional brain imaging have provided exciting and informative insights into the functional neuroanatomy and neurochemistry of schizophrenia. Using MR spectroscopy, it has been possible to examine in vivo brain metabolism and to relate observed changes to physiological processes occurring at a cellular level. Positron emission tomography and single photon emission computed tomography have revealed disturbances of cerebral blood flow and glucose metabolism in patients with schizophrenia. More recently, these tools have also proved most useful in studying the relative receptor occupancy of typical and atypical antipsychotic medications.