Protein oxidation in aging brain.
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Aging↗
Biomedical subjects
W R Markesbery
Publications and source records attributed to W R Markesbery.
Monoaminergic and cholinergic synaptic markers in the nucleus basalis of Meynert (nbM): normal age-related changes and the effect of heart disease and Alzheimer's disease.
Neurotransmitter markers for acetylcholine, serotonin (5-HT), and dopamine (DA) were measured in autopsied human nucleus basalis of Meynert (nbM) from nondemented individuals without heart disease (non-HD) (age range, 4-84 years; n = 77), nondemented individuals with heart disease (HD) (age range, 57-92 years; n = 23), and individuals with Alzheimer's disease (AD) (age range, 59-92 years; n = 22). No significant differences in any chemical marker were found between age-matched HD and non-HD individuals. The activities of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE), and [3H]spiperone binding were regionally distributed within the nbM in control (non-HD) subjects less than 54 years of age. The activity of AChE, 5-[3H]HT binding, and the content of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 5-HT were regionally distributed in the nbM in non-HD, HD, and AD subjects more than 54 years of age. The binding of [3H]spiperone was regionally distributed in the nbM in HD and AD subjects more than 54 years of age, only. Activity of ChAT and AChE, content of 5-HT, 5-HIAA, and DA, binding of 5-[3H]HT, and the turnover number for DA (ratio of HVA/DA) all decreased with increasing age in the non-HD control population. The content of HVA, binding of [3H]spiperone, and the turnover number for 5-HT (ratio of 5-HIAA/5-HT) did not change with increasing age. Significant reductions in ChAT and AChE activities were found in AD nbM compared with postmortem interval- and age-matched HD and non-HD individuals. The reduction of 5-HT and 5-HIAA content and [3H]spiperone binding in individuals with AD of all ages suggests a loss of functional serotonergic innervation of the nbM. Dopaminergic synaptic markers were less affected in AD nbM, although turnover numbers for both DA and 5-HT were increased in AD. Receptor upregulation in response to presynaptic deficits did not occur for DA or 5-HT.
Acetylcholinesterase↗
Cortical biopsy in Alzheimer's disease: diagnostic accuracy and neurochemical, neuropathological, and cognitive correlations. Intraventricular Bethanecol Study Group.
Neurochemical assessments were performed on biopsy samples taken from the right frontal lobe of patients diagnosed with Alzheimer's disease (AD), before the implantation of a ventricular catheter and pump assembly for the infusion of bethanechol chloride as an experimental therapy. The pathologically diagnosed patients with AD (n = 35; mean age, 67 +/- 1.5 yr) were compared with a group of samples from normal age-equivalent autopsied controls (n = 22; mean age, 68 +/- 2 yr) and autopsied AD brains (n = 11; mean age, 73 +/- 2 yr). Samples were assayed for choline acetyltransferase (ChAT), acetylcholinesterase, binding to [3H]quinuclidinyl benzilate as an index of total muscarinic cholinergic binding, and [3H]pirenzepine binding as an index of M1 cholinergic receptor subtype binding. Mean levels of ChAT activity were decreased in the biopsied patients to 36% of age-matched autopsied controls. The loss of ChAT activity correlated significantly with the Mini-Mental State Examination, an index of global cognitive function. Mean ChAT activity in autopsied AD cortex was further decreased compared with controls, indicating continuous decline through the course of the disease. Acetylcholinesterase followed a similar, less dramatic decline. No differences were found in [3H]quinuclidinyl benzilate binding or [3H]pirenzepine binding between biopsied and autopsied controls. Neuritic plaque counts did not correlate with either the Mini-Mental State Examination or ChAT activity in the biopsy specimens.(ABSTRACT TRUNCATED AT 250 WORDS)
Acetylcholinesterase↗
Perivascular siderophages in skeletal muscle from a patient with diabetic neuropathy.
Hemosiderin deposition in skeletal muscle histiocytes is uncommon but has been occasionally noted in hemochromatosis, hemosiderosis and Waldenstrom's macroglobulinemia. The purpose of this report is to describe the light microscopic and ultrastructural characterization of this abnormality in a patient with diabetes mellitus. A 56-year-old diabetic male presented with paresthesias and intermittent diffuse lower extremity myalgias. Neurologic examination was remarkable only for diminished vibratory sense in the toes, diminished deep tendon reflexes, and ankle-level stocking distribution hypalgesia. There was no clinical evidence of hemochromatosis and laboratory studies ruled out Waldenstrom's macroglobulinemia. Muscle biopsy showed modest variability in myofiber diameter with a few scattered angular atrophic type II fibers. There were numerous collections of granular pigment-containing histiocytes in endomysial and perimysial perivascular areas and marked thickening of blood vessels walls. The histiocytic pigment was bright blue with the Prussian blue stain. No pigment was seen in the myofibers. Ultrastructural examination revealed numerous perivascular histiocytes filled with hemosiderin containing granules of variable size and density and marked thickening of capillary walls with striking reduplication of basement membranes. A modest number of subsarcolemmal paracrystalline mitochondrial inclusions were present. X-ray dispersion analysis of the histiocytic pigment material confirmed the presence of iron in the lysosomal granules.
Blood Vessels↗
Familial influence on plaque formation in the beagle brain.
Aged canines exhibit central neuropathological changes strikingly similar to those seen in patients with Alzheimer's disease. In this study, brain tissue from pure bred beagles raised in a controlled environment were examined for Alzheimer-like pathology. The mean age of the animals was 15.6 years. The incidence of plaques among these 29 dogs was 65.5%. Of the 19 samples that demonstrated Alzheimer-like pathology, 18 were characterized as diffuse and one as neuritic. Plaque density was found to be independent of age. Plaque numbers were highest in the perirhinal cortex and the adjacent temporal cortex. Familial influence on plaque development is supported by congruence within 15 of the 16 litters examined (p < 0.001). In this environmentally controlled group the diffuse plaques were rarely converted to the dense neuritic plaques found in Alzheimer's disease.
Aging↗
Alzheimer disease brain extract stimulates branching of laminin-mediated neuronal processes.
Patients with Alzheimer disease (AD) suffer mental deterioration associated with neurofibrillary tangle and senile plaque formation in the brain. Here we have determined the effects of brain extracts from normal and from AD patients on neuronal process formation by a pheochromocytoma (PC-12) and a neuroblastoma x glioma hybrid cell line (NG108-15). PC12 cells show a dose-related stimulation of branching of neuronal processes by AD brain extracts with cells cultured on a laminin substrate. The neurotrophic effects of extracts of AD brains may be related to the abnormal sprouting and neurofibrillary tangle formation observed in the brain in this disorder.
Adrenal Gland Neoplasms↗
Image analysis of neuropil threads in Alzheimer's, Pick's, diffuse Lewy body disease and in progressive supranuclear palsy.
Neuropil threads (NT) in the middle temporal gyrus (MTG) were quantitated by computerized image analysis from five patients each with Alzheimer's disease (AD), Pick's disease (PD), and diffuse Lewy body disease (DLBD), four patients with progressive supranuclear palsy (PSP), and five cognitively normal control subjects (24 patients total). All disease groups met clinical and pathological criteria for their respective diseases. The DLBD subjects did not have pathological features of AD. Using the Gallyas silver method, the percentage of cortical area occupied by NT was calculated for each case examined and compiled for each group. Intergroup comparison revealed the percentage of cortical area occupied by NT as follows: AD, 6.87%; PSP, 1.12%; PD, 0.37%; DLBD, 0.04%; control 0.02%. The evaluation disclosed a significance level of p < 0.0001 when AD was compared to control, PD and DLBD cases and a p < 0.001 when compared to PSP. There was no statistically significant difference between control-DLBD, control-PD, control-PSP, DLBD-PSP, PD-PSP, or PD-DLBD cases (p > 0.05). These data indicate the density of neocortical threads is much greater in AD than in other dementing disorders. It also suggests that NT are not related to the intellectual decline in PD, DLBD, and PSP.
Aged↗
Brain aluminum in Alzheimer's disease using an improved GFAAS method.
Aluminum (Al) has been determined in autopsy brain samples (20 mg, dry weight) from 10 histologically verified Alzheimer's disease (AD) patients and 10 neurologically normal controls using an improved graphite furnace atomic absorption method. The method makes use of a potassium dichromate matrix modifier to circumvent interferences to the Al determination by the high levels of phosphorus and alkali metals in brain tissue. Brain regions studied included middle frontal gyrus, hippocampus, inferior parietal lobule, and the superior and middle temporal gyri. Small, but significant (p < 0.05) elevations of Al were observed in AD hippocampus, inferior parietal lobule and superior and middle temporal gyri, compared to corresponding control tissues. In contrast to other reports in the literature, no extremely high Al levels (> 20 micrograms/g, dry weight) were observed in our samples. Our highest value for Al in AD brain was 8.0 micrograms/g. These results suggest that there is a small focal increase of Al in specific regions of AD brain compared to age-matched controls. The fact that the increase is small, coupled with the analytical difficulties of accurate bulk sample Al determinations by any technique in the brain matrix, may account for the discordant literature reports for Al in AD brain.
Aged↗
Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease.
The relationship between Alzheimer disease (AD) and aging is not currently known. In this study, postmortem frontal- and occipital-pole brain samples were obtained from 16 subjects with AD, 8 age-matched controls, and 5 young controls. These samples were analyzed both for protein oxidation products (carbonyl) and the activities of two enzymes vulnerable to mixed-function oxidation, glutamine synthetase and creatine kinase. Glutamine synthetase is more sensitive to mixed-function oxidation than creatine kinase. Carbonyl content rises exponentially with age, at double the rate in the frontal pole compared with the occipital pole. Compared with young controls, both aged groups (AD and age-matched controls) have increased carbonyl content and decreased glutamine synthetase and creatine kinase activities, which are more marked in the frontal than occipital pole in all instances. We conclude that protein oxidation products accumulate in the brain and that oxidation-vulnerable enzyme activities decrease with aging in the same regional pattern (frontal more affected than occipital). However, only glutamine synthetase activity distinguishes AD from age-matched controls: Because glutamine synthetase activity is differentially reduced in the frontal pole in AD, we suggest that AD may represent a specific brain vulnerability to age-related oxidation.
Adult↗
Alterations in brain monoamine oxidase activity in aging, Alzheimer's disease, and Pick's disease.
Alzheimer's disease (AD) and Pick's disease (PD) are dementing disorders of unknown origin. Monoamine oxidase (MAO) is important in the metabolism of a number of monoamine neurotransmitters. This study investigates MAO activity in aging, AD, and PD in frontal and temporal poles, nucleus basalis of Meynert (nbM), and hypothalamus. Regional variations in the activity of the two MAO forms (A and B) were found in aging, AD, and PD. Age-related increase of MAO-B was found in all four areas of the brain, and MAO-A was increased in the nbM and temporal pole. In AD, MAO-B was decreased in the nbM and increased in the temporal pole, while MAO-A was increased in the hypothalamus and frontal pole. In PD, MAO-B was decreased in the nbM and increased in the hypothalamus, while MAO-A was increased in the hypothalamus and decreased in the nbM and temporal pole. These data indicate that with regard to MAO activity, AD and PD are dissimilar diseases and neither strictly follows age-related changes.
Aged↗
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.
Acetylcholinesterase↗
Comments on vascular dementia.
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Age Factors↗
Trace element imbalances in isolated subcellular fractions of Alzheimer's disease brains.
Concentrations of 13 trace elements (Ag, Br, Co, Cr, Cs, Fe, Hg, K, Na, Rb, Sc, Se, Zn) in isolated subcellular fractions (whole brain, nuclei, mitochondria, microsomes) of temporal lobe from autopsied Alzheimer's disease (AD) patients and normal controls were determined utilizing instrumental neutron activation analysis. Comparison of AD and controls revealed elevated Br (whole brain) and Hg (microsomes) and diminished Rb (whole brain, nuclear and microsomes), Se (microsomes) and Zn (nuclear) in AD. The elevated Br and Hg and diminished Rb are consistent with our previous studies in AD bulk brain specimens. Comparison of element ratios revealed increased Hg/Se, Hg/Zn and Zn/Se mass ratios in AD. Se and Zn play a protective role against Hg toxicity and our data suggest that they are utilized to detoxify Hg in the AD brain. Overall our studies suggest that Hg could be an important toxic element in AD. Whether Hg deposition in AD is a primary or secondary event remains to be determined.
Aged↗
A randomized trial of surgery in the treatment of single metastases to the brain.
To assess the efficacy of surgical resection of brain metastases from extracranial primary cancer, we randomly assigned patients with a single brain metastasis to either surgical removal of the brain tumor followed by radiotherapy (surgical group) or needle biopsy and radiotherapy (radiation group). Forty-eight patients (25 in the surgical group and 23 in the radiation group) formed the study group; 6 other patients (11 percent) were excluded from the study because on biopsy their lesions proved to be either second primary tumors or inflammatory or infectious processes. Recurrence at the site of the original metastasis was less frequent in the surgical group than in the radiation group (5 of 25 [20 percent] vs. 12 of 23 [52 percent]; P less than 0.02). The overall length of survival was significantly longer in the surgical group (median, 40 weeks vs. 15 weeks in the radiation group; P less than 0.01), and the patients treated with surgery remained functionally independent longer (median, 38 weeks vs. 8 weeks in the radiation group; P less than 0.005). We conclude that patients with cancer and a single metastasis to the brain who receive treatment with surgical resection plus radiotherapy live longer, have fewer recurrences of cancer in the brain, and have a better quality of life than similar patients treated with radiotherapy alone.
Adult↗
Congenital myopathy and cardiomyopathy with identical ultrastructural changes.
A 7-day-old girl with congenital hypotonia and unexplained episodes of bradycardia had a broad spectrum of similar skeletal muscle and myocardial degenerative ultrastructural abnormalities. Ultrastructural studies showed obliteration of cross striations, myofilament disorganization, streaming, smearing, clumping, and zigzag Z-band deformities. A decrease in glycogen, mitochondria, and T-tubular system occurred in the regions showing Z-band abnormalities of both skeletal muscle and myocardium. Concurrent structural cardiomyopathy should be considered in patients with congenital myopathies, particularly with unexplained cardiac conduction abnormalities or contractile insufficiency. Ultrastructural evaluation of skeletal and cardiac muscle may be necessary to define such disorders.
Biopsy↗
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.
Adenosine Triphosphate↗
Transplantation of pituitary grafts fail to restore immune function and to reconstitute the thymus glands of aged mice.
There is evidence to indicate that the neuroendocrine and immune systems can interact. Thus, neuroendocrine hormones can modulate a variety of immune functions and there have been attempts to manipulate the neuroendocrine system of aged animals to enhance immune function. We have previously shown that the transplantation of a syngeneic pituitary gland under the kidney capsule of young adult mice elevates serum prolactin and enhances immune responsiveness. In the present study pituitary glands were transplanted under the kidney capsule of 22-month-old mice to determine if this maneuver can enhance a number of immunologic parameters. The results demonstrate that aged animals bearing transplanted pituitary grafts for 10 days did not exhibit any enhancement in their primary antibody response to sheep red blood cells, splenic T or B-cell mitogen responsiveness or restoration of thymic architecture. When these immunologic assessments are performed on animals bearing pituitary grafts for 28 days, the IgM and IgG primary antibody responses and splenic T-cell responsiveness are enhanced but repopulation of the thymus still does not occur. Importantly, this enhancement does not restore immunocompetence to levels observed in young mice.
Aging↗
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.
Amyotrophic Lateral Sclerosis↗