Imbalances of trace elements related to oxidative damage in Alzheimer's disease brain.

Four elements that have been implicated in free-radical-induced oxidative stress in Alzheimer's disease (AD) were measured by instrumental neutron activation analysis (INAA) in seven brain regions from 58 AD patients and 21 control subjects. A statistically significant elevation of iron and zinc was observed in multiple regions of AD brain, compared with controls. Mercury was elevated in AD in most regions studied, but the high variability of mercury levels in both AD and control subjects prevented the AD-control difference from reaching significance. Selenium, a protective agent against mercury toxicity, was significantly elevated only in AD amygdala. The elevation of iron and zinc in AD brain has the potential of augmenting neuron degeneration through free radical processes.

Iron, selenium and glutathione peroxidase activity are elevated in sporadic motor neuron disease.

Oxygen free radical damage is strongly implicated in the pathogenesis of familial motor neuron disease (MND) associated with mutation of the Cu/Zn superoxide dismutase gene, and may be relevant in sporadic MND. Selenium (Se) and iron (Fe) have important roles in free radical metabolism. Using neutron activation analysis we have demonstrated significant elevation of Se and Fe in lumbar spinal cord in MND cases (38) compared to controls (22). Analysis of enzymes involved in free radical scavenging showed a significant and specific increase in the activity of the selenoprotein enzyme glutathione peroxidase in MND spinal cord.

31P magnetic resonance spectroscopy in Alzheimer's and Pick's disease.

Previous studies have suggested a defect in phosphorus metabolism in Alzheimer's disease (AD) gray matter. We have studied phosphorus metabolites in both gray and white matter in autopsy specimens of nine subjects with late-stage AD, three with Pick's disease and seven age-matched controls. Phosphorus metabolites sugar phosphate (SU), phosphomonoester (PME), phosphodiester (PD), and inorganic phosphate (PI) were quantified as mole percentages in regional neocortical specimens using nuclear magnetic resonance spectroscopy. Senile plaque (SP) and neurofibrillary tangle (NFT) counts were determined in adjacent cortical sections. In the inferior parietal lobule gray and white matter, mole percentage normalized PME, and PD were significantly greater than control values in both AD and Pick's disease. A significant correlation was found between PD and NFT in AD parietal gray matter. Our data indicates that phosphorus metabolite alterations are present in two cortical degenerative diseases and are not likely to be specific for AD.

Altered serotonergic and cholinergic synaptic markers in Pick's disease.

Choline acetyltransferase and acetylcholinesterase activities as well as serotonin and imipramine binding were determined in the hypothalamus, nucleus basalis of Meynert, and frontal and temporal poles of subjects with Pick's disease. Choline acetyltransferase activity was decreased in the hypothalamus and nucleus basalis of Meynert, and acetylcholinesterase activity was decreased in the nucleus basalis of Meynert only. Serotonin binding was decreased in all sites but the nucleus basalis of Meynert, and imipramine binding was altered only in the frontal pole. Comparison with previous reports of Alzheimer's disease indicates that with respect to these synaptic markers, Alzheimer's disease and Pick's disease are not similar.

31P spectroscopy in experimental embolic stroke: correlation with infarct size.

Serial 31P nuclear magnetic resonance spectra were acquired from the brain in 19 rats following microsphere embolization of the right internal carotid artery. The brains were sectioned and stained with 2,3,5-triphenyltetrazoline chloride 6 h post-embolization to visualize infarcted areas. There was a narrow dosage range for the effect of embolism measured by maximum decline in pH at 20 min, mortality, and infarct size. This narrow range effect may be due to occlusion of collateral channels by the 16 micron microspheres. There was a strong correlation between decline in pH at 20 min post-embolization and infarct size (r2 = 0.76); this decline was the best early marker for eventual infarct in our study. This animal model for macroscopically heterogenous brain ischemia may be useful for the evaluation of therapeutic interventions in stroke, and as an aid in the interpretation of phosphorus spectra from mixed volumes of ischemic and non-ischemic brain.

Trace element imbalances in amyotrophic lateral sclerosis.

Concentrations of 15 elements were determined by instrumental neutron activation analysis in brain, spinal cord, blood cells, serum and nails of Amyotrophic Lateral Sclerosis (ALS) patients and appropriately matched control subjects. Several significant imbalances were detected in trace element levels in ALS samples compared to control samples. Some of these changes are probably secondary to the loss of tissue mass, especially in spinal cord. However the widespread changes observed in Hg and Se levels in ALS tissues deserve special attention. The significance of these alterations in trace element levels in relation to the pathogenesis of ALS is discussed.

Alzheimer's disease. Aminergic-cholinergic alterations in hypothalamus.

To better understand the role of the hypothalamus in Alzheimer's disease (AD), we have measured dopamine, norepinephrine (NE), and serotonin (5HT) levels, tritiated spiperone and tritiated serotonin blinding, and choline acetyltransferase (ChAT) and acetylcholinesterase activity in seven subregions of the hypothalamus from 18 normal control subjects and ten patients with AD. We have found a significant reduction of 5HT in the anterior hypothalamus, lateral hypothalamus, and posterior lateral hypothalamus and a decline in spiperone binding in the anterior hypothalamus of patients with AD. The ChAT activity was found to be diminished only in the posterior lateral hypothalamus of patients with AD. No NE or dopamine alterations were found in any region of the AD hypothalamus. In the normal hypothalamus, dopamine, NE, and 5HT were found to be regionally distributed. Our study documents region-specific neurotransmitter abnormalities in the AD hypothalamus and raises the question of the relationship of these changes, especially in 5HT, to some of the noncognitive clinical alterations observed in AD.

Laminar organization of cholinergic circuits in human frontal cortex in Alzheimer's disease and aging.

Cholinergic enzyme activity (choline acetyltransferase, CAT; acetylcholinesterase, AChE) and muscarinic cholinergic receptor density were measured in frontal cortex (Brodmann's area 9) of normal patients over the life span and in brains of patients with Alzheimer's disease (AD). CAT, but not AChE activity, declined with normal aging. Significant loss of CAT and AChE activity occurred in the AD brains, but later onset AD was associated with less severe loss of frontal cortex CAT activity. The majority of normal CAT activity resided in lamina I, II, and upper lamina III; CAT loss in AD resulted in large losses from all depths, most notably the upper cortical layers. AChE did not precisely correspond to the localization of CAT; loss of AChE in AD was consistent across all six laminae. No differences were seen in muscarinic cholinergic receptor binding between AD and age-matched controls; the distribution of binding was equal in all layers of normal frontal cortex, and no laminar differences were detected in distribution of cholinergic receptors between normal and AD samples.

Age-associated alteration of serotonergic synaptic neurochemistry in rat rostral hypothalamus.

Levels of monoamines and metabolites in rostral and caudal hypothalamic fragments of young (3-4 months) and old (25-26 months) Fischer 344-rats were compared. There were no differences between fragments of young animals. In senescent rats, 5-hydroxyindoleacetic acid (5HIAA) increased in both rostral and caudal hypothalamus. The ratio 5HIAA/5HT (serotonin), an index of serotonin turnover, increased only rostrally. This age-related increase of 5HIAA/5HT in rostral hypothalamus was associated with a decrease in [3H]-spiperone binding. There were no age-related changes of MAO-A activity in the hypothalamus or of serum tyrosine or tryptophan levels.

Hypothalamic-immune interactions. Effect of hypophysectomy on neuroimmunomodulation.

Electrolyte destruction of certain nuclei of the brain cause specific structural and functional changes in the immune system. Lesions in the preoptic-anterior hypothalamic area result in thymic involution and a decrease in the number and blastogenic reactivity of splenocytes. In contrast, lesions in the hippocampus increase thymic and splenic mitogenic responsiveness and cellularity. Hypophysectomy abrogates all changes in splenocyte number and function induced by hypothalamic and limbic lesions. The effects of ablating the hippocampus and amygdaloid complex on thymocyte number and function also are abolished. Hypothalamic lesions in hypophysectomized animals result in an increase in the number of thymocytes but suppressed mitogenic activity. These data indicated that neuroimmunomodulation is mediated predominantly but not exclusively by the pituitary gland.

Hypothalamic-immune interactions. I. The acute effect of anterior hypothalamic lesions on the immune response.

Rats with electrolytic anterior hypothalamic lesions show changes in lymphoid tissue cellularity and a decrease in the response to concanavalin A (Con A). This effect manifests itself maximally 4 days after lesioning, with a return to normal by day 14. The changes are not mediated through the release of corticosteroids. These data indicate the presence of a neuroendocrine pathway that is capable of modulating immune function.