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Biomedical subjects

J W Pettegrew

Publications and source records attributed to J W Pettegrew.

At least 19 recordsLinked to original sources
PubMed1995

Biological correlates of slow wave sleep deficits in functional psychoses: 31P-magnetic resonance spectroscopy.

Deficits in slow wave sleep (SWS) are consistently seen in schizophrenia and related psychotic disorders. However, the pathophysiological significance of this finding is uncertain. In 19 patients with psychotic illness, sleep and 31P-magnetic resonance spectroscopy (MRS) studies were carried out before the patients began medication treatment. Polysomnographic studies were carried out in 2-3 consecutive nights. MRS studies were performed with a surface coil and a depth-resolved pulse sequence focusing on the dorsal prefrontal cortex. Phosphomonoesters were correlated with visually scored delta and Stage 4 sleep, as well as with automated delta wave counts. An inverse relation was also seen between negative symptoms scores and SWS. The association between decreases brain anabolic processes (reflected by decreased PME) and decreased SWS may be related either to processes of accelerated aging or to developmentally mediated alterations in cortical synaptic pruning, postulated to underlie the pathophysiology of functional psychoses.

Adult↗
PubMed1995

A comparison of stereology and segmentation techniques for volumetric measurements of lateral ventricles in magnetic resonance imaging.

Lateral ventricular volumes were measured on magnetic resonance imaging (MRI) scans by independent raters in 18 subjects (11 psychotic patients and 7 healthy control subjects) with two different approaches: a point-counting stereological (PCS) technique and a computerized technique based on segmentation algorithms. The correlation between the two techniques was very high (r = 0.96), and phantom studies showed good validity for both approaches. These findings and the technical simplicity of the PCS technique support its potential use for MRI morphometric measurements.

Cerebral Ventricles↗
PubMed1995

Inactivity of phosphoethanolamine, an endogenous GABA analog decreased in Alzheimer's disease, at GABA binding sites.

Phosphoethanolamine (PE) is a metabolite of the phospholipid metabolism which is decreased in Alzheimer's disease brain. PE shows a strong structural similarity to the inhibitory neurotransmitter, GABA, and the GABAB receptor partial agonist, 3-amino-propylphosphonic acid. The ability of PE to compete for binding to GABAA and GABAB binding sites was investigated. GABAA sites were studied using [3H]SR-95531 and [3H]muscimol. GABAB sites were studied using [3H]GABA in the presence of isoguvacine to saturate GABAA sites. Total [3H]GABA binding was also examined. PE showed little activity at any of the GABA binding sites investigated. PE was most potent at GABAB sites, but the IC50 of 7.5 +/- 0.75 mM was considerably higher than its maximal physiologic concentration of approximately 1.5 mM. The efficient exclusion of PE from GABA binding sites may be an important physiologic mechanism in the control of inhibitory neurotransmission. The structural basis for this exclusion is discussed in reference to the GABAB partial agonist 3-amino-propylphosphonic acid.

Alzheimer Disease↗
PubMed1995

Magnetic resonance spectroscopy and its application to aging and Alzheimer's disease.

This is a review of magnetic resonance (MR) spectroscopy and its application to aging and Alzheimer's disease (AD). Examinations of perchloric acid extracts of AD brain tissue by MR spectroscopy reveal elevated levels of phosphomonoesters, phosphodiesters, and glutamate accompanied by reduced levels of N-acetyl-L-aspartate compared with extracts from controls. These metabolicalterations may be an indication of accelerated membrane phospholipid metabolism, glutamate neurotoxicity, and neuronal loss in AD brain that is not seen in normal aging. In vivo 31P MR spectroscopy studies of AD indicate that levels of phosphomonoesters are elevated early in the course of AD, which may be a causative molecular neuropathologic event. In vivo MR spectroscopy is a powerful technique to investigate the molecular neuropathology of the disease, to follow the progression of AD, and to assess the efficacy of experimental therapies.

Adolescent↗
PubMed1994

NMR identification of the formic acid-modified residue in Alzheimer's amyloid protein.

The beta/A4-amyloid protein (beta/A4) and many synthetic fragments of this protein have proved to be very difficult to solubilize, leading to the use of relatively harsh chemical methods, most notably, formic acid. This treatment has previously been shown to cause a covalent modification of this peptide. In this study, one- and two-dimensional NMR techniques are used to show that the nature of this covalent modification is formation of a formate ester to a serine residue. This finding is consistent with our previously reported kinetic studies of formic acid-induced modification of beta/A4 and further illustrates the potential danger of solubilizing fragments of beta/A4 in formic acid. Alternative methods of solubilization are discussed.

Amino Acid Sequence↗
PubMed1993

Erythrocyte membrane phospholipids in psychotic patients.

Thin layer chromatography and laser densitometry were used to examine erythrocyte membrane phospholipid composition in 13 medication-free patients with schizophrenia or schizoaffective disorder and 11 healthy control subjects. The patient group had significantly decreased levels of phosphatidylethanolamine and a significant increase in sphingomyelin. The patient group also showed a trend toward decreased levels of phosphatidylinositol bisphosphate. Levels of phosphatidylcholine and lysophosphatidylcholine did not significantly differ between groups. There were no significant effects of age, body mass index, or gender on any of the phospholipid parameters. The observed alterations may point to abnormalities in key membrane-related functions, including signal transduction and ion transport.

Adult↗
PubMed1993

Frontal lobe metabolism and cerebral morphology in schizophrenia: 31P MRS and MRI studies.

The relation between frontal lobe membrane phospholipid metabolism as measured by 31Phosphorus magnetic resonance spectroscopy (31P MRS) and cerebral morphology as measured on magnetic resonance images (MRI) was examined in nine first episode neuroleptic naive schizophrenic patients. Total corpus callosal area was significantly correlated with phosphodiester concentration. When examined separately, this relation was confined to the rostral quartile (genu) of the corpus callosum. The pathophysiological significance of this finding is discussed in relation to neurodevelopmental hypotheses of schizophrenia.

Adult↗
PubMed1992

Molecular insights into schizophrenia.

A number of studies have demonstrated alterations in the structure and function of the frontal cortex in some schizophrenic patients. The possible etiology and pathogenesis of these abnormalities are unknown, but genetic and developmental causes are frequently mentioned. Recent in vivo 31P NMR studies of the dorsal prefrontal cortex have been conducted in eleven neuroleptic naive, first episode schizophrenic patients and compared with normal controls of comparable age, educational level and parental educational level. The findings in the schizophrenic patients are different from those of normal IQ adult autistic patients of comparable age and Alzheimer's patients but similar to normal elderly controls. These studies show decreased frontal lobe utilization of adenosine triphosphate in the schizophrenic patients which suggests a hypoactive dorsal prefrontal cortex. In addition, indices of membrane phospholipid metabolism are altered in the schizophrenic patients. However, the findings in the schizophrenic patients are quite similar to those observed in normal elderly controls and to those that normally occur to a lesser degree during adolescence. The phospholipid alterations observed in the schizophrenic patients are compatible with either premature aging or altered timing and exaggeration of the regressive events which occur during normal brain development. The changes in high-energy phosphate metabolism observed in the schizophrenic patients may prove to be state dependent, but the changes in membrane phospholipid metabolism could be related to molecular changes that precede the onset of clinical symptoms and brain structural changes in schizophrenia. These findings suggest new avenues of thinking about the pathogenesis and treatment of schizophrenia.

Aging↗
PubMed1992

N-acetyl-L-aspartate and other amino acid metabolites in Alzheimer's disease brain: a preliminary proton nuclear magnetic resonance study.

We used proton nuclear magnetic resonance spectroscopy in this preliminary study of perchloric acid extracts of 12 Alzheimer's disease (AD) and five control brain samples to measure the relative levels of taurine, aspartate, glutamine, glutamate, gamma-aminobutyric acid (GABA), and the putative neuronal marker, N-acetyl-L-aspartate (NAA). We found no significant changes in taurine, aspartate, or glutamine. NAA was lower in AD compared with control, and this decrease correlated with the number of senile plaques and neurofibrillary tangles in adjacent tissue sections. GABA levels also were lower in AD brain. Glutamate levels were greater in AD than control and showed a close, inverse correlation with NAA levels. These findings suggest that the decrease in NAA reflects neuronal loss and that remaining neurons could be exposed to a relative excess of glutamate and a relative lack of GABA. If present in the neurotransmitter pool, this imbalance could result in neurotoxic cell damage. This hypothesis is further supported by in vitro and in vivo phosphorus 31 nuclear magnetic resonance findings.

Aged↗
PubMed1991

Alterations in brain high-energy phosphate and membrane phospholipid metabolism in first-episode, drug-naive schizophrenics. A pilot study of the dorsal prefrontal cortex by in vivo phosphorus 31 nuclear magnetic resonance spectroscopy.

In this pilot study, membrane phospholipid and high-energy phosphate metabolism were studied in the dorsal prefrontal cortex of 11 drug-naive, first-episode schizophrenic patients and compared with those of 10 healthy control volunteers comparable in age, education, and parental education. The schizophrenic patients had significantly reduced levels of phosphomonoesters and inorganic orthophosphate and significantly increased levels of phosphodiesters and adenosine triphosphate compared with the controls. The levels of phosphocreatine and adenosine diphosphate did not differ in the two subject groups. The adenosine triphosphate and inorganic orthophosphate findings suggest functional hypoactivity of the dorsal prefrontal cortex. The phosphomonoester and phosphodiester findings are compatible with either premature aging or an exaggeration of normal programmed regressive events occurring in the neural systems sampled.

Adult↗
PubMed1991

Actions of phosphomonoesters on CA1 hippocampal neurons as revealed by a combined electrophysiological and nuclear magnetic resonance study.

Phosphomonoesters (PMEs), precursors of membrane phospholipids, are found in high levels in the developing brain and Alzheimer's disease brain. The present study details the neurophysiological and metabolic effects of acute PME elevation on the Fisher 344 rat in vitro hippocampal slice. Two abundant PMEs, phosphoethanolamine (PE) and L-phosphoserine (PS), reliably altered properties of synaptic transmission at the Schaffer collateral/commissural-CA1 cell synapse. Specifically, PE reversibly depressed the amplitude of population EPSPs at millimolar concentrations but had no effect at micromolar concentrations. PS had biphasic effects on population EPSPs, inducing first a reduction followed by an enhancement of response amplitude. In contrast to PE, the effects of PS were not reversible; population EPSPs were augmented during the wash of PS, and the CA3 region generated evoked (but not spontaneous) epileptiform discharges. 31P nuclear magnetic resonance spectroscopy revealed enhanced slice uptake of PS compared to PE. There was no significant effect of PE on slice high-energy phosphates but incubation with PS significantly lowered slice phosphocreatine (PCr) and ATP concentrations. These observations indicate that the slice uptake of PS could be energy requiring and the enhanced response amplitude observed at 5 mM PS also could produce a drain on high-energy phosphates. Possible modes of PME action on hippocampal physiology are discussed.

Adenosine Triphosphate↗
PubMed1991

Possible roles of L-phosphoserine in the pathogenesis of Alzheimer's disease.

L-Phosphoserine is a membrane metabolite that is elevated in Alzheimer's disease brain. This compound has close structural similarity to L-glutamate. Electrophysiological studies indicate that L-phosphoserine has an acute inhibitory effect, but a delayed excitatory action. A hypothesis is developed based on pharmacological and electrophysiological studies that suggest that the inhibition may be mediated through presynaptic inhibition of L-glutamate release or perhaps antagonism of postsynaptic kainic acid receptors. The mechanism of the delayed excitation may lie in the tendency of L-phosphoserine to mimic the action of L-2-amino-4-phosphonobutyric acid, a blocker of chloride- and calcium-sensitive L-glutamate transport. L-Phosphoserine has also been found to be a competitive antagonist at the N-methyl-D-aspartate recognition site and an antagonist of metabotropic receptor-mediated hydrolysis of inositol phospholipids. Because of these actions, there are several potentially important implications for the elevation of L-phosphoserine in Alzheimer's disease, including production memory impairment through presynaptic inhibition of L-glutamate release or blockade of postsynaptic N-methyl-D-aspartate receptors and/or blockade of certain L-glutamate transport sites resulting in increased L-glutamate levels in the synaptic cleft.

Alzheimer Disease↗
PubMed1991

Al-ATP as an intracellular carrier of Al(III) ion.

1. Using 27Al and 31P NMR spectroscopy in conjunction with an Al lactate aqueous reagent at pH 7.2, Al complexes of ATP and of phospholipids were characterized in synthetic-aqueous and organic-phospholipid chemical systems and in the intact human red blood cell. 2. The observed 31P NMR chemical shifts of the Al-ATP complex in aqueous laboratory preparations or the intact human red blood cell were, respectively, alpha phosphate, -11.53 delta; beta phosphate, -22.65 delta; and gamma phosphate, -10.95 delta. 3. The observed complexed 27Al chemical shift was -2.22 delta. 4. The relative affinities for Al of the phospholipids determined from 31P NMR spectroscopic titrations were PA much greater than Cl much greater than PS greater than PG approximately equal to PI greater than PE plus approximately equal to PE much greater than SPH greater than PC.

Adenosine Triphosphate↗
PubMed1991

L-phosphoserine, a metabolite elevated in Alzheimer's disease, interacts with specific L-glutamate receptor subtypes.

L-Phosphoserine is one of the phosphomonoesters elevated in Alzheimer's disease brain and has close structural similarity to L-glutamate. This study attempts to define precisely the actions of L-phosphoserine at L-glutamate receptor subtypes. L-Phosphoserine is shown to bind to N-methyl-D-aspartate and kainic acid receptor subtypes, but not to the quisqualic acid subtype. Studies of [3H]MK-801 binding in the presence and absence of L-glutamate and glycine show L-phosphoserine to be a competitive N-methyl-D-aspartate antagonist. The IC50 of L-phosphoserine in these studies varies from 373 to 721 microM. This may indicate a physiologically relevant action of L-phosphoserine in Alzheimer's disease brain because whole brain concentrations may reach over 1 mM.

2-Amino-5-phosphonovalerate↗