Kanagasabai Panchalingam

Brain Membrane Phospholipid Alterations in Alzheimer's Disease

Studies have demonstrated alterations in brain membrane phospholipid metabolite levels in Alzheimers 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 Aβ peptide.

Alterations of cerebral metabolism in probable Alzheimer's disease: A preliminary study

Previous in vitro and in vivo 31P MRS studies of Alzheimers disease patients have revealed alterations in membrane phospholipid metabolism and PET studies have shown alterations in glucose and oxidative metabolism. This study of probable Alzheimers disease patients demonstrates severity dependent alterations in measures of both high-energy phosphate and membrane phospholipid metabolism. Mildly demented Alzheimers patients compared to the controls, have increases in the levels of phosphomonoesters, decreases in the levels of phosphocreatine and probably adenosine diphosphate, and an increased oxidative metabolic rate. As the dementia worsens, the levels of phosphocreatine and adenosine diphosphate increase, the levels of phosphomonoesters decrease, and the oxidative metabolic rate decreases. The phosphomonoester findings replicate previous findings and provide a new dimension to the molecular pathology of Alzheimers disease, implicating basic defects in membrane metabolism. The changes in oxidative metabolic rate suggest the AD brain is under energetic stress. The changes in energy metabolites with increasing dementia could be a consequence of nerve terminal degeneration and are consistent with previous PET findings. 31P MRS provides new diagnostic and metabolic insights into this disease and would be a noninvasive method to follow the progression of the disease and the metabolic response to therapeutic interventions.

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 Alzheimers disease (AD) and five control brain samples to measure the relative levels of taurine, aspartate, glutamine, glutamate, γ-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.

A preliminary 31P MRS study of autism: Evidence for undersynthesis and increased degradation of brain membranes

In this pilot study, brain high energy phosphate and membrane phospholipid metabolism were investigated in the dorsal prefrontal cortex of 11 high-functioning autistic adolescent and young adult men (the age range is 12-36 years) and 11 age-, gender-, IQ, race- and socioeconomic status-matched normal controls using in vivo 31P nuclear magnetic resonance spectroscopy (MRS). The autistic group had decreased levels of phosphocreatine and esterified ends (alpha ATP + alpha ADP + dinucleotides + diphosphosugars) compared to the controls. When the metabolite levels were compared within each subject group with neuropsychologic and language test scores, a common pattern of correlations was observed across measures in the autistic group, but not in the control group. As test performance declined in the autistic subjects, levels of the most labile high energy phosphate compound and of membrane building blocks decreased, and levels of membrane breakdown products increased. No significant correlations were present with age in either group or with IQ in the control group, suggesting that these findings were not the consequence of age or IQ effects. This pilot study provides tentative evidence of alterations in brain energy and phospholipid metabolism in autism that correlate with the neuropsychologic and language deficits. The findings are consistent with a hypermetabolic energy state and undersynthesis of brain membranes and may relate to the neurophysiologic and neuropathologic abnormalities in autism.

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.

31P nuclear magnetic resonance study of the brain in Alzheimer's disease.

The histopathological hallmarks of Alzheimers disease have long been considered to be neurofibrillary tangles (NFT) and neuritic (senile) plaques (SP). Neither of these structures, however, are unique to Alzheimers disease, and both probably represent end-stage markers of the disorder. NFT have been demonstrated in many disorders; SP occur in small numbers with normal aging. Evidence is presented for elevation of phosphomonoesters (PME) in Alzheimers brain compared to non-Alzheimers diseased controls and normal controls. The PME detected by 31P nuclear magnetic resonance (NMR) spectroscopy of autopsy brain are predominantly anabolic precursors of membrane phospholipids. Elevated PME could be secondary to a metabolic block at the rate-limiting enzyme in membrane phospholipid synthesis, which is cytidine triphosphate (CTP): phosphocholine (or phosphoethanolamine) cytidyltransferase (EC 2.7.7.15). Elevated PME could also be secondary to decreased breakdown of PME by phospholipase D activity. Since CTP: phosphocholine cytidyltransferase is inactivated by phosphorylation and since there is independent evidence for hyperphosphorylation of tau and MAP-2 proteins in AD brain, enhanced protein kinase activity could be a common factor. Preliminary evidence suggests that PME could interact with N-methyl-D-aspartate receptors and potentially act as false neurotransmitters. Further studies will be needed to investigate these possibilities.

Clinical and neurochemical effects of acetyl-L-carnitine in Alzheimer's disease.

In a double-blind, placebo study, acetyl-L-carnitine was administered to 7 probable Alzheimers disease patients who were then compared by clinical and 31P magnetic resonance spectroscopic measures to 5 placebo-treated probable AD patients and 21 age-matched healthy controls over the course of 1 year. Compared to AD patients on placebo, acetyl-L-carnitine-treated patients showed significantly less deterioration in their Mini-Mental Status and Alzheimers Disease Assessment Scale test scores. Furthermore, the decrease in phosphomonoester levels observed in both the acetyl-L-carnitine and placebo AD groups at entry was normalized in the acetyl-L-carnitine-treated but not in the placebo-treated patients. Similar normalization of high-energy phosphate levels was observed in the acetyl-L-carnitine-treated but not in the placebo-treated patients. This is the first direct in vivo demonstration of a beneficial effect of a drug on both clinical and CNS neurochemical parameters in AD.

Changes in Brain Energy and Phospholipid Metabolism During Development and Aging in the Fischer 344 Rat

The effects of brain development and aging on high-energy phosphate and membrane phospholipid metabolism were studied from birth to senescence in the Fischer 344 rat using 31P nuclear magnetic resonance spectroscopy. Marked developmental and smaller aging-related changes were observed in brain high-energy phosphates, phospholipid precursors and phospholipid breakdown products. The biochemical changes correlate with known histological and electrophysiological changes occurring in the brain during development (neuritic sprouting and onset of brain electrical activity) and aging (loss of dendritic processes). These findings provide a framework for interpreting the effects of physiological insults during different developmental and aging periods.

Analysis of magnetic resonance spectra by mole percent: Comparison to absolute units

A variety of metabolites present in perchloric acid extracts of brain tissue were measured by 1H and 31P magnetic resonance spectroscopy (MRS) and HPLC in the same tissue sample and the MRS results were expressed both in terms of mole % and mumole/g based on an internal standard. The levels of 16 metabolites were compared by linear regression analysis and the mole % results were found to correlate very well with the results expressed as mumole/g. To compare the two units under typical experimental conditions, the percent change in metabolites in a group of Alzheimers disease brains was compared to a control group using both units. The results were essentially identical for the mole % and mumole/g methods. We conclude that the use of the mole % method of expressing MRS data yields results which are equivalent to those expressed in absolute units and suggest that, for in vivo MRS studies, use of the mole % method is preferable because fewer artifacts, such as partial volume effects, are introduced.

Changes in brain membrane phospholipid and high-energy phosphate metabolism precede dementia

A 52-year-old Caucasian male was followed with Mattis and 31P MRS examinations every 6 months for 33 months. At entry into the study, the subject had a normal clinical examination and normal Mattis scores but had alterations in MRS measures of membrane phospholipid and high-energy phosphate metabolism indistinguishable from those previously reported in mildly demented AD patients. After 33 months of follow-up, the subject had clinical and Mattis findings suggestive of possible incipient dementia and after 46 months of follow-up there was sufficient cognitive decline to make the diagnosis of dementia with a frontal lobe preponderance. The findings in this subject support the contention that alterations in brain membrane phospholipid and high-energy metabolism can be noninvasively detected by 31P MRS years before any clinical manifestations of the disease.