i(3)so3-galactosylceramide and Schizophrenia

Cortical neuronal dysfunction has been proposed to underlie the psychopathology and cognitive dysfunction of schizophrenia. Previously we have reported altered sphingolipid and N-acylphosphatidylserine (NAPS) metabolism in the frontal cortex in schizophrenia. We continue to expand these investigations to define the biochemical basis for these critical neuropathologies.. We undertook a targeted high resolution mass spectrometric analysis to validate our previous reports of elevated sphingolipids and NAPS in the frontal cortex of a new cohort of schizophrenia subjects. Furthermore we expanded these analyses to include ceramides, N-acylphosphatidylethanolamines (NAPE), and N-acylethanolamines (NAE). In the same tissue samples we examined N-acetylaspartylglutamate (NAAG), a modulator of excitatory amino acid transmission, hypothesized to be involved in the pathology of schizophrenia.. We repeated our observations of elevated sulfatides in the frontal cortex in schizophrenia. An in-depth analysis of other sphingolipids revealed decrements in ceramide levels and increased levels of lactosylceramides. NAPS also were found to be augmented in schizophrenia as we previously reported. In addition, levels of NAPES, established biomarkers of neuronal stress, were elevated while their metabolites, NAEs were decreased. With regard to excitatory amino acid neurotransmission, NAAG levels were decreased by 50% while the metabolic precursor, N-acetylaspartate was unaltered.. Our data support the concept of cortical neuronal dysfunction in schizophrenia as indicated by altered metabolism of structural sphingolipids and NAAG, a modulator of excitatory amino acid neurotransmission.

Topics: Adult; Female; Frontal Lobe; Humans; Lipidomics; Male; Mass Spectrometry; Metabolomics; Middle Aged; Neurons; Oxidative Stress; Phosphatidylserines; Psychopathology; Schizophrenia; Schizophrenic Psychology; Sphingolipids; Sulfoglycosphingolipids; Synaptic Transmission

Our previous lipidomics studies demonstrated elevated sulfatides, plasmalogens, and N-acylphosphatidylserines in the frontal cortex of schizophrenia subjects. These data suggest that there may be an abnormal function of glycosynapses in schizophrenia. We further examined the disease and anatomical specificity of these observations.. We undertook a targeted lipidomics analysis of plasmalogens, sulfatides, and N-acyl-phosphatidylserines in the frontal cortex obtained from schizophrenia, bipolar, and ALS subjects and the cerebellum of schizophrenia subjects.. We demonstrate that sulfatides, plasmalogens, and N-acyl-phosphatidylserines are significantly elevated in the frontal cortex of patients suffering from schizophrenia and bipolar depression but not in ALS patients. These lipids were unchanged in the cerebellum of subjects with schizophrenia.. Our data suggest that dysfunction of oligodendrocyte glycosynapses may be specific to limbic circuits in schizophrenia and that this dysfunction is also detected in bipolar depression, suggesting that these disorders possess several common pathophysiological features.

Topics: Adult; Aged; Aged, 80 and over; Amyotrophic Lateral Sclerosis; Bipolar Disorder; Cerebellum; Female; Frontal Lobe; Humans; Male; Middle Aged; Oligodendroglia; Phosphatidylserines; Plasmalogens; Schizophrenia; Sulfoglycosphingolipids

Membrane lipids are important mediators of neuronal function. In a postmortem study, we measured membrane lipid components in the left thalamus of schizophrenic patients. This region might play an important role in the pathophysiology of schizophrenia and has not been studied thus far with respect to its membrane lipid composition.. The study included 18 chronic schizophrenic patients and 23 healthy control subjects. Using lipid extraction and thin-layer chromatography, we measured membrane phospholipids, galactocerebrosides 1 and 2, and sulfatides in thalamus homogenate.. The main membrane phospholipid phosphatidylcholine and the major myelin membrane components sphingomyelin and galactocerebrosides 1 and 2 were found to be decreased in schizophrenic patients. In contrast, phosphatidylserine was increased. These lipid contents did not correlate with postmortem intervals and medication doses. There was no difference in the membrane phospholipids lysophosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, and phosphatidylglycerol or in sulfatides.. Our results confirm findings of magnetic resonance imaging, postmortem, and gene expression studies. They support the notion of an increased phospholipid breakdown in schizophrenia as a sign for decreased myelination and oligodendrocyte dysfunction.

Topics: Aged; Aged, 80 and over; Analysis of Variance; Autopsy; Case-Control Studies; Female; Galactosylceramides; Humans; Male; Membrane Lipids; Middle Aged; Phosphatidylcholines; Phosphatidylserines; Schizophrenia; Sphingomyelins; Sulfoglycosphingolipids; Thalamus

Metachromatic leukodystrophy (MLD) is a rare inherited neurodegenerative disease associated with a defect in the catabolism of sulphatide (galactocerebroside-sulphate) which accumulates in the nervous system. MLD can be diagnosed biochemically by demonstrating deficiency in the activity of the enzyme arylsulphatase A (ASA) and an excess of sulphatide in urine and tissues. Clinically adult MLD may present as a schizophrenic-like psychosis, which typically develops years before the onset of neurologial signs which are not inevitable. Urinary ASA was investigated in 99 chronic hospitalized psychiatric patients (including 77 schizophrenics). Thirteen showed reduced ASA activity. Of the nine who were available for further study, only one evinced reduced ASA activity in other tissues (for example, leukocytes and cultured fibroblasts). However, there was no evidence of sulphatidurea with impaired sulphatide hydrolysis in his intact cultured fibroblasts. Therefore, he tested negative for MLD. This biochemical profile is known as pseudosulphatase deficiency. The possible relationship of pseudosulphatase deficiency to schizophrenic-like conditions is discussed.

Topics: Cerebroside-Sulfatase; Diagnosis, Differential; Humans; Leukodystrophy, Metachromatic; Neurocognitive Disorders; Schizophrenia; Schizophrenic Psychology; Sulfoglycosphingolipids

Metachromatic leukodystrophy (MLD) is a disease caused by a deficiency of the enzyme sulfatide sulfatase, also known as arylsulfatase A (ASA). We compared the activity of this enzyme in adult psychiatric patients and normal volunteers using nitrocatechol sulfate (ASA-NCS) and cerebroside sulfate (ASA-CS) as substrates. Our results showed that ASA-NCS activity in urine and leukocytes was significantly lower in psychiatric than in normal individuals, but that there were no differences between these two groups in the sulfatide excretion in urine or the ASA-CS activity in leukocytes. There was no correlation between enzyme activity in urine and in leukocytes, indicating that activity in urine does not truly reflect the levels of the enzyme in tissues. The correlation between ASA-NCS and ASA-CS activity in leukocytes was poor (0.51 for psychiatric patients and 0.59 for normals), suggesting that for a valid measure of the enzyme activity the assays should be carried out with CS as substrate. Results of our study also indicate that in 39 of the 145 psychiatric patients studied, the ASA-CS activity in leukocyte was less than 4 nmoles/mg protein/hr, which is below 50% of the normal means, whereas only one of the 30 normal subjects had a value this low. The presence of low levels of ASA-CS activity in a significantly large number of adult patients with varying psychiatric manifestations suggests that such patients may be asymptomatic carriers of the sulfatidase defect (heterozygotes for MLD), and that behavioral and functional disturbances in these patients may at least in part be related to sulfatidase deficiency. The significance of the ASA-NCS abnormality (reduction) in psychiatric patients is unclear.

Topics: Cerebroside-Sulfatase; Female; Humans; Huntington Disease; Intellectual Disability; Leukocytes; Leukodystrophy, Metachromatic; Male; Mental Disorders; Neurocognitive Disorders; Schizophrenia; Sulfatases; Sulfoglycosphingolipids

An autopsy case of adult metachromatic leukodystrophy (MLD) manifested clinically as schizophrenic psychosis is reported. A 50-year-old man developed progressive mental changes 10 years before his death, and later manifested a schizophrenic syndrome without neurologic deficits or EEG changes. After his death from uremia neuropathology disclosed MLD with demyelination accentuated in the frontal lobes and abundant metachromatic deposits in the preserved areas of cerebral white matter. Neurochemical examination of the demyelinated frontal area showed reduced concentration of cerebrosides and sulfatides, decreased amounts of total lipids in the tissue, and an increase of sulfatides, and particularly of their cerebron fractions in lipid extract. The problems of adult forms of MLD with prolonged course are discussed with special reference to cases showing mainly psychiatric syndromes.

Topics: Atrophy; Brain; Cerebrosides; Diagnostic Errors; Electroencephalography; Frontal Lobe; Humans; Hydrocephalus; Leukodystrophy, Metachromatic; Male; Middle Aged; Schizophrenia; Sulfoglycosphingolipids