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W R Markesbery

Publications and source records attributed to W R Markesbery.

At least 109 records · Page 6Linked to original sources
PubMed1996

Copper, iron, and zinc imbalances in severely degenerated brain regions in Alzheimer's disease: possible relation to oxidative stress.

Copper (Cu), iron (Fe), and zinc (Zn) levels in five different brain regions (amygdala, hippocampus, inferior parietal lobule, superior and middle temporal gyri, and cerebellum) were determined by instrumental neutron activation analysis (INAA) in samples from Alzheimer's disease (AD) patients and age-matched control subjects. A significant decrease in Cu, and significant increases in Zn and Fe were found in AD hippocampus and amygdala, areas showing severe histopathologic alterations in AD. None of these elements were significantly imbalanced in the cerebellum which is minimally affected in AD.

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PubMed1995

Serum zinc, senile plaques, and neurofibrillary tangles: findings from the Nun Study.

Zinc appears to have a role in binding amyloid precursor protein in vitro, but it is not known whether zinc plays a role in senile plaque formation in vivo in humans. Serum zinc concentrations were available from 12 sisters who died in the Nun Study, a longitudinal study of aging and Alzheimer's disease. Fasting serum zinc concentrations, determined approximately 1 year before death, showed moderate to strong negative correlations with senile plaque counts in seven brain regions. In all brain regions combined, the age-adjusted negative correlations with serum zinc were statistically significant for total senile plaques and diffuse plaques, and suggestive for neuritic plaques. Thus serum zinc in the normal range may be associated with low senile plaque counts in the elderly.

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PubMed1995

Neutron activation analysis of trace elements in motor neuron disease spinal cord.

Levels of 10 trace elements were analysed in autopsied lumbar spinal cords of 38 motor neuron disease patients and 22 control subjects using instrumental neutron activation analysis. Statistically significant elevations of iron, selenium and zinc, and depletions of mercury and cesium were found in the spinal cords of motor neuron disease patients compared with control subjects. No significant correlations were found between disease duration, clinical severity or lumbar motor neuron counts and iron and selenium levels, suggesting that accumulation of these elements occur early as well as late in the disease process and therefore are not a consequence of end stage pathology. Increased iron in motor neuron disease spinal cord could act to enhance formation of reactive oxygen species. Our study supports the free radical hypothesis of neuron degeneration in motor neuron disease.

Adult↗
PubMed1995

Elemental imbalances in the olfactory pathway in Alzheimer's disease.

Concentrations of 11 trace elements were determined in 56 control and 98 Alzheimer's disease (AD) olfactory bulb, olfactory tract, olfactory trigone, piriform cortex and amygdala specimens by instrumental neutron activation analysis. Iron and zinc were significantly elevated and bromine was significantly depleted in olfactory regions of AD patients, compared with normal age-matched control subjects. Elevated iron could possibly play a role in neuronal degeneration in AD by enhancing reactive free radical formation.

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PubMed1995

Neurotrophic factors attenuate glutamate-induced accumulation of peroxides, elevation of intracellular Ca2+ concentration, and neurotoxicity and increase antioxidant enzyme activities in hippocampal neurons.

Exposure of cultured rat hippocampal neurons to glutamate resulted in accumulation of cellular peroxides (measured using the dye 2,7-dichlorofluorescein). Peroxide accumulation was prevented by an N-methyl-D-aspartate (NMDA) receptor antagonist and by removal of extracellular Ca2+, indicating the involvement of NMDA receptor-induced Ca2+ influx in peroxide accumulation. Glutamate-induced reactive oxygen species contributed to loss of Ca2+ homeostasis and excitotoxic injury because antioxidants (vitamin E, propyl gallate, and N-tert-butyl-alpha-phenylnitrone) suppressed glutamate-induced elevation of intracellular Ca2+ concentration ([Ca2+]i) and cell death. Basic fibroblast growth factor (bFGF), nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF), but not ciliary neurotrophic factor, each suppressed accumulation of peroxides induced by glutamate and protected neurons against excitotoxicity. bFGF, NGF, and BDNF each increased (to varying degrees) activity levels of superoxide dismutases and glutathione reductase. NGF increased catalase activity, and BDNF increased glutathione peroxidase activity. The ability of the neurotrophic factors to suppress glutamate toxicity and glutamate-induced peroxide accumulation was attenuated by the tyrosine kinase inhibitor genistein, indicating the requirement for tyrosine phosphorylation in the neuro-protective signal transduction mechanism. The data suggest that glutamate toxicity involves peroxide production, which contributes to loss of Ca2+ homeostasis, and that induction of antioxidant defense systems is a mechanism underlying the [Ca2+]i-stabilizing and excitoprotective actions of neurotrophic factors.

Animals↗
PubMed1995

Familial progressive subcortical gliosis: presence of prions and linkage to chromosome 17.

Progressive subcortical gliosis (PSG) is a sporadic and familial dementing disease characterized pathologically by astrogliosis at the cortex-white matter junction, a feature present in some prion diseases. With immunocytochemical and Western blot analyses, we investigated the presence of deposits of the prion protein (PrP) and of the protease-resistant PrP isoform, the hallmarks of prion diseases, in six affected members of two large kindreds with PSG. The coding region of the PrP gene was sequenced and chromosomal linkage determined. We demonstrated "diffuse" PrP plaques in the cerebral cortex of two subjects from one kindred and protease-resistant PrP fragments in four of the five subjects examined. We found no mutation in the coding region of the PrP gene. Moreover, the disease was linked to chromosome 17 and not to chromosome 20, where the PrP gene resides. The familial form of PSG is the first human genetic disease characterized by the presence of protease-resistant PrP that lacks a mutation in the coding region of the PrP gene. The linkage to chromosome 17 suggests that other genes are involved in the PrP metabolism. Whether the protease-resistant PrP plays a primary or secondary role in the pathogenesis of this form of PSG remains to be determined.

Adult↗
PubMed1995

Elevated thiobarbituric acid-reactive substances and antioxidant enzyme activity in the brain in Alzheimer's disease.

We determined levels of thiobarbituric acid-reactive substances (TBARS), a measure of lipid peroxidation, and the activity of the antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), glutathione reductase (GSSG-R), and catalase (CAT) in the amygdala, hippocampus, pyriform cortex, superior and middle temporal gyri, inferior parietal lobule, middle frontal gyrus, occipital pole, and cerebellum of 13 Alzheimer's disease (AD) and 10 control brains. Levels of TBARS were elevated in all AD brain regions except the middle frontal gyrus, and elevation levels reached statistical significance in the hippocampus and pyriform cortex and marginal significance in the amygdala of AD subjects compared with age-matched controls. Significant elevation of GSH-Px activity was present in AD hippocampus compared with control. Moderate but statistically insignificant elevations of GSH-Px activity also were present in the amygdala and pyriform cortex in AD. GSSG-R activity was significantly elevated in the amygdala and hippocampus in AD subjects compared with controls. CAT activity was significantly elevated in AD hippocampus and superior and middle temporal gyri. SOD levels were elevated in all brain regions in AD patients compared with controls, although none of these elevations reached statistical significance. Antioxidant enzyme activities were significantly elevated where lipid peroxidation was most pronounced, suggesting a compensatory rise in antioxidant activity in response to increased free radical formation. This study supports the concept that the brain in AD is under increased oxidative stress and demonstrates that the oxidative changes are most pronounced in the medial temporal lobe, where histopathologic alterations are most severe.

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PubMed1994

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.

Glutathione Peroxidase↗
PubMed1994

Application of electron energy loss spectroscopy and electron spectroscopic imaging to aluminum determination in biological tissue.

Electron energy loss spectroscopy (EELS) is a high spatial resolution electron microscopic technique with the potential to quantify elements at the subcellular level. The presence of each element is demonstrated by the electron energy loss edge at the energy characteristic of that element. The area of the edge may indicate the quantity of element present. Electron spectroscopic imaging (ESI) is a similar technique generating graphic images of elemental localization in the specimens. An ESI of an aluminum (Al)-loaded rabbit hippocampus showed Al only in pyramidal cell lysosomes, but no EELS edge could be obtained. To determine the sensitivity of EELS for Al and to be able to adjust the instrument to optimal operating conditions, standards containing 50-5000 ppm Al were produced. An Al-chloride: dicyclohexano-18-crown-6 (Al: crown) complex was synthesized. The purity of the complex was confirmed by nuclear magnetic resonance (NMR) spectroscopy and the percentage of Al in the complex was determined by electrothermal atomic absorption spectroscopy (ETAAS). The complex was introduced into a biological tissue embedding resin (Spurr medium) and appeared to be compatible with the resin at Al concentrations < or = 500 ppm. EELS signals from the Al K edge could be obtained at a spatial resolution of 3.3 nm in a 30-nm thick section from 2.78 x 10(-21) g of Al, representing a sample concentration of 1% Al.

Aluminum↗
PubMed1994

Presence of neuronal proteins in serially cultured cells from autopsy human brain.

Cells that contain the high (NF-H) and medium (NF-M) molecular weight neurofilaments and neuron-specific enolase (NSE) have been cultured from human brain (Brodmann frontal area 9 and hippocampus) obtained at routine autopsy. Three of these cultures (from a 52-year-old man with vascular dementia, a 75-year-old man with Alzheimer's disease, and an 80-year-old normal woman) have been propagated to passage 12-14 and studied in detail. Cellular morphology was pleomorphic and consistent with a relatively low level of differentiation, by both light microscopic and ultrastructural examination. Immunocytochemical reactivity in a characteristic filamentous pattern was observed with monoclonal antibodies to nonphosphorylated epitopes of NF-H and NF-M as well as with redundant antibody probes specific for NF-H and NF-M. Immunoblotting studies confirmed the presence of NF-H and NF-M. Immunocytochemistry and Immunoblotting also demonstrated the presence of NSE, but not of glial fibrillary acidic protein or other glial markers. Immunocytochemical studies also indicated the presence of proline hydroxylase, an enzyme found in fibroblasts but not neurons. These studies indicate that cells can be cultured from autopsy human brain which are not neurons but nevertheless express molecules used as markers (NF-H, NF-M, and NSE) of adult neurons in vivo and in culture.

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PubMed1994

Familial progressive subcortical gliosis.

We report clinical and pathologic findings from two kindreds afflicted with a familial form of progressive subcortical gliosis. The disorder segregated as an autosomal dominant trait. Onset was in the presenium and the course was slowly progressive. Affected individuals initially manifested personality change, degeneration of social ability, disinhibition, psychotic symptoms, memory impairment, or depression. Later, all developed progressive dementia, frequently associated with verbal stereotypy, decreased speech output, echolalia, or manifestations of the human Klüver-Bucy syndrome. Terminal clinical manifestations included profound dementia, frequently with mutism, dysphagia, and extrapyramidal signs. Autopsy of seven end-stage patients revealed generalized cerebral atrophy, predominantly involving the white matter of the frontal and temporal lobes. Microscopically, prominent fibrillary astrocytosis was present in the subcortical white matter and in the subpial and deep layers of the overlying cerebral cortex. These changes were most pronounced in the frontal and temporal lobes, especially in the cingulate gyri and insulae. Mild cortical neuronal loss accompanied the gliosis, but no myelin loss was evident. The claustra and substantia nigra also showed severe astrocytosis and degenerative changes. Amyloid deposits and neuronal cytoskeletal inclusions were absent.

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PubMed1993

Comparison of the effects of elevated intracellular aluminum and calcium levels on neuronal survival and tau immunoreactivity.

Both calcium and aluminum have been implicated in the cell damage and death that occurs in several neurodegenerative disorders including Alzheimer's disease (AD). We examined the effects of experimentally elevated intraneuronal levels of aluminum ([Al]i) and/or calcium ([Ca2+]i) on neuronal degeneration and antigenic alterations in the microtubule-associated protein tau in cell cultures of rat hippocampus and human cerebral cortex. Exposure of cultures to Al3+ alone (200 microM) for up to 6 d did not result in neuronal degeneration. Neurons exposed to the divalent cation ionophore A23187 degenerated within 4 h when Ca2+ was present in the culture medium whether or not Al3+ was present. Measurements of [Ca2+]i using the calcium indicator dye fura-2 demonstrated a direct relationship between increased [Ca2+]i and neuronal degeneration. In contrast, neurons did not degenerate when exposed to A23187 in the presence of Al3+ and the absence of Ca2+, despite a 10-fold elevation in [Al]i as measured by laser microprobe mass spectrometry. Calcium influx, but not aluminum influx, elicited antigenic changes in tau similar to those seen in AD neurofibrillary tangles. Neurons exposed to glutamate in the presence of Al3+ but in the absence of Ca2+ were not vulnerable to injury. Finally, increased [Al]i occurred in neurons that degenerated as the result of exposure to glutamate indicating that aluminum associates with degenerating neurons. Taken together these data indicate that, in contrast to increased [Ca2+]i, elevated [Al]i may not induce degeneration or antigenic changes in tau.

Aluminum↗
PubMed1993

Laser microprobe analysis of brain aluminum in Alzheimer's disease.

Aluminum (Al) levels were measured in the cytoplasm and nucleus of 241 neurofibrillary tangle (NFT)-bearing neurons, in 217 NFT-free neurons and adjacent neuropil from 7 autopsy-confirmed Alzheimer's disease (AD) patients, and in 316 normal neurons from 5 control subjects, by laser microprobe mass spectrometry. Grand mean Al levels (dry weight basis) in AD samples were 2.93 +/- 1.24 micrograms/gm for NFT-bearing neuron cytoplasm, 3.54 +/- 1.39 micrograms/gm for NFT-bearing neuron nuclei, 2.31 +/- 1.09 micrograms/gm for NFT-free neuron cytoplasm, and 3.23 +/- 1.09 micrograms/gm for NFT-free neuron nuclei. Control values were 1.85 +/- 0.78 micrograms/gm for cytoplasm and 2.01 +/- 0.93 micrograms/gm for nuclei. The differences between corresponding regions of AD NFT-bearing, AD NFT-free, and control neurons were not significant (p > 0.05, analysis of variance). Al levels in neuropil were identical for AD and control samples at 2.16 +/- 0.93 micrograms/gm. In contrast to some literature reports, we found very few (< 2.5%) extremely high Al values (> 20 micrograms/gm, dry weight) on a cellular basis in AD samples. AD neurons did exhibit a higher number of Al values (9.6-14.3%) that were > 3 sigma above the corresponding control means, than did control neurons (1.3-1.6%), indicating that small elevations of Al may exist in patients with AD. Our data suggest that any Al accumulation in patients with AD is small and generalized in both NFT-free and NFT-bearing neurons and that analyses of large bulk brain samples are likely to have AD/control differences masked by the large amount of unaffected neuropil sampled.

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PubMed1993

Lipidized medulloblastoma in adults.

We describe the clinical, imaging, histologic, immunohistochemical, and ultrastructural features as well as the DNA ploidy analysis of two primitive neuroectodermal neoplasms demonstrating prominent cytoplasmic lipid accumulation originating in the posterior fossa of adults. These two tumors most likely exemplify a variant of medulloblastoma with heavily lipidized cells and support the postulated pluripotentiality of primitive neuroectodermal neoplasms. Recognition of this entity as a phenotypic variant of medulloblastoma will militate against diagnostic confusion with other entities that may contain cells with lipoblastic or adipocytic differentiation.

Cerebellar Neoplasms↗
PubMed1993

Morphometric analysis of microglia in Alzheimer's disease.

HLA-DR-immunoreactive microglia were quantitated in the middle temporal gyrus of five late-stage patients with Alzheimer's disease (AD) and five age-matched control subjects using LN3 immunocytochemistry and computerized morphometric image analysis. The grand mean numerical density of HLA-DR-immunoreactive microglia in AD (403.86/mm2) was significantly larger than in the five control subjects (193.33/mm2) (p < 0.0001). The grand mean cross-sectional area of HLA-DR-immunoreactive microglia in AD subjects (222.90 microns2) was significantly larger than in control subjects (121.59 microns2) (p < 0.0001). The percentage of total microglia that were large activated microglia was much greater in AD (47.9%) than in control subjects (15.2%). The grand mean percent of the cortical area occupied by HLA-DR-immunoreactive microglia in AD (9.02%) was significantly greater than in controls (2.35%) (p < 0.0001). Microglia were present in greater numbers in the outer three cortical laminae in both AD and controls. The striking increase in activated microglia in the neocortex and their role in the inflammatory response and possible secretion of neurotoxins could be important in neuron degeneration in AD.

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