Alzheimer's disease--a mini review.
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Alzheimer Disease↗
Biomedical subjects
W R Markesbery
Publications and source records attributed to W R Markesbery.
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.
Acetylcholinesterase↗
Neuronal RNA in relation to Alz-50 immunoreactivity in Alzheimer's disease.
Both defective nucleic acid metabolism/protein synthesis and the expression of an abnormal antigen recognized by the Alz-50 antibody may be involved in the neuronal degeneration of Alzheimer's disease (AD). A multiparametric analysis involving Alz-50 immunocytochemistry and azure B--RNA microdensitometry was developed to compare nucleic acid alterations in Alz-50-positive neurons to those in Alz-50-negative neurons of the brain of AD patients. Alz-50-immunoreactive neurons of the hippocampal endplate (Rose's H3-H5 fields) and the subiculum exhibited significantly lower (by approximately 30%) total RNA contents than negative neurons of the corresponding region. The mean RNA content of Alz-50-positive neurons of the AD brain was also reduced in comparison to that of Alz-50-negative neurons of age-matched, nondemented controls, whereas there were no significant differences between negative neurons of AD patients and controls. The hippocampus of nondemented controls was also found to contain Alz-50-immunoreactive neurons, although 20- to 30-fold fewer than the hippocampus of AD patients. In the controls, there was also a tendency toward reduced RNA levels in Alz-50-positive versus -negative neurons. These data suggest a relationship between Alz-50 immunoreactivity and defective nucleic acid metabolism in the AD brain.
Alzheimer Disease↗
Fatal adenovirus meningoencephalitis in a bone marrow transplant patient.
We describe a bone marrow transplant patient with fatal subacute adenovirus meningoencephalitis, the first such patient reported. Neuropathological examination revealed unique, bilaterally symmetrical degeneration in the inferomedial temporal cortex, amygdaloid nuclei, hippocampi, hypothalamus, and some brainstem nuclei. Viral intranuclear inclusions were noted in these areas by light microscopy and confirmed by electron microscopy. Identification was authenticated by viral culture and the isolation of adenovirus from cerebral cortical tissues, and further confirmed by immunofluorescence and serological methods.
Adenoviridae Infections↗
Astrocyte RNA in relation to neuronal RNA depletion in Alzheimer's disease.
A new double-staining procedure, in which the techniques of immunocytochemistry of glial fibrillary acidic protein (GFAP) and quantitative microdensitometry of azure B-RNA were combined, was used to study nucleic acid alterations in fibrous astrocytes in Alzheimer's disease (AD). RNA contents of GFAP-positive cells of the hippocampal endplate (Rose's H3-H5 fields) and the dentate gyrus molecular layer were determined in ten autopsy-proven AD patients (ages 51-88) and ten age-matched, non-demented controls. In addition, RNA contents of pyramidal neurons of the endplate were examined. While there were no differences in RNA contents of astrocytes of either region between AD patients and controls, neuronal RNA was markedly depleted. These data suggest that astrocytes maintain protein synthetic capabilities in AD and that RNA loss is limited to the neuronal compartment.
Aged↗
Trace element imbalances in hair and nails of Alzheimer's disease patients.
The concentrations of 17 elements in the hair and nails of 180 Alzheimer's disease (AD) and control subjects have been determined by instrumental neutron activation analysis (INAA). Comparisons of trace element levels of properly matched AD and control groups revealed significant imbalances in the concentrations of six elements (Br, Ca, Co, Hg, K, and Zn) between disease and control groups. It is noteworthy that each of these has previously been shown by our group, or others, to be altered in some AD brain region(s). Geometric means for each element in both hair and nails of AD and control subjects are presented, and significant differences noted. The significance of these alterations with regard to the possible role of trace elements in the etiology of AD is discussed.
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Regional brain trace-element studies in Alzheimer's disease.
Alzheimer's disease (AD) brain trace-element imbalances in the amygdala, hippocampus and nucleus basalis of Meynert (nbM) are found in most cases to be consistent with those previously reported in samples derived principally from AD cerebral cortex (Ehmann et al., 1986). The elevation of mercury in AD nbM, as compared to age-matched controls, is the largest trace-element imbalance observed to date in AD brain. In addition to the general confirmation of imbalances for Cs, Hg, N, Na, P, and Rb noted previously in cerebral cortex samples, imbalances for Fe, K, Sc, and Zn were observed in two regions and one region also exhibited imbalances for both Co and Se. Persistent imbalances for the univalent cations Na, K, Rb and Cs support arguments for a membrane abnormality in AD. The data presented here also provide the first comprehensive simultaneous multi-element determinations in both control and AD nbM.
Alzheimer Disease↗
Neuronal RNA in relation to neuronal loss and neurofibrillary pathology in the hippocampus in Alzheimer's disease.
Topographic analyses were performed on the distribution of neuronal RNA loss in relation to local neuronal loss and neurofibrillary degeneration in the hippocampal region of brains of patients with Alzheimer's disease (AD). Compared to age-matched controls, pyramidal neuronal RNA was depressed (p less than 0.0001) in all areas of the hippocampus examined in AD, viz., the endplate (33%), Rose's H2 field (30%), Rose's H1 field (37%) and the subiculum (46%). Significant neuronal loss was observed in Rose's H1 field and the subiculum but not in the endplate or Rose's H2 field. The frequency of neurofibrillary tangle-bearing neurons was enhanced in all four regions of AD brains, the number of involved neurons being markedly greater in Rose's H1 field and the subiculum than in the endplate and Rose's H2 field. Overall, the data indicate the existence of a generalized disturbance in RNA metabolism within pyramidal neurons in the hippocampus in AD, occurring in regions of minimal (endplate, Rose's H2 field) as well as those of extensive (Rose's H1 field, subiculum) pathological alterations. Although there is focal accentuation of RNA depletion in the latter, the marked RNA depletion in regions of minimal pathologic change suggests that this effect is largely unrelated to local neuronal loss or neurofibrillary degeneration.
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In situ analysis of neostriatal RNA and chromatin in Alzheimer's disease.
Scanning-integrating microdensitometry of azure B-RNA- and Feulgen-Schiff-stained tissue sections was used to measure neostriatal neuronal RNA levels and susceptibility of neuronal and oligodendrocyte chromatin to acid hydrolysis in Alzheimer's disease (AD) patients and controls. AD was associated with neuronal RNA depletion (17 to 23%) in both caudate nucleus and putamen. While neuronal chromatin was found to be more acid-labile than that of the oligodendrocytes, there were no differences in either cell type between AD and controls. These data support the existence of a macromolecular disturbance (RNA loss) occurring within neostriatal neurons, perhaps related to the extrapyramidal dysfunction of AD, but fail to demonstrate that an alteration in chromatin is responsible for this effect.
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Iodine-123 HIPDM brain imaging findings in subacute spongiform encephalopathy (Creutzfeldt-Jakob disease).
Decreased perfusion of the left frontal and left temporoparietal cortex has been shown in [123I] HIPDM planar and single photon emission computed tomographic images of a patient with Creutzfeldt-Jakob disease (CJD) that was proven by brain biopsy and subsequent autopsy. An EEG showed diffuse, periodic discharges most prominent to the left hemisphere. Concurrent head computed tomography (CT), nuclear magnetic resonance (NMR), and cerebral angiographic studies were negative. Abnormalities demonstrated by [123I]HPDM imaging and by EEG may represent changes in neurophysiological and neurochemical status while cerebral angiography, CT, and possibly NMR register only anatomic or structural lesions. Premortem diagnosis of CJD depends on brain biopsy; the availability of the [123I] HIPDM study may provide regional cerebral neurochemical and neurophysiological information, guiding or avoiding brain biopsy in the appropriate clinical setting.
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Alzheimer's disease: monoamines and spiperone binding reduced in nucleus basalis.
Levels of dopamine and serotonin, and of their precursors and metabolites, were measured in the nucleus basalis of Meynert (nbM) of patients with Alzheimer's disease and control patients. [3H]Spiperone binding to membrane homogenates of the nbM, indicative of both dopaminergic and serotonergic receptors, was also measured. The nbM from patients with Alzheimer's disease showed significant decreases in both spiperone binding and in the levels of dopamine and serotonin but no decrease in either tyrosine or tryptophan levels. These data indicate a loss of both dopaminergic and serotonergic synapses in the nbM of patients with Alzheimer's disease.
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Invasiveness in primary intracranial tumors: Part 1. An experimental model using cloned SV40 virus-produced hamster brain tumors.
This report presents an experimental model for study of the cellular and molecular biology of invasiveness in tumors. It uses SV40 virus for the production of primary intracranial tumors that are invasive for normal brain and vary markedly and predictably in this invasiveness. Cell cultures of dissociated 1- to 2-day-old Syrian hamster cerebral cortex (Cx), brain stem (Bs), cerebellar hemisphere (Cbh), and cerebellar vermis (Cbv) were transformed with SV40 virus and inoculated intracerebrally into newborn hamsters. All 368 animals that developed intracranial tumors were killed, and tumor was taken for histological and immunofluorescence studies, assessment of extent of invasiveness, and preparation of cell cultures from which cells were cloned by dilution plating or growth in soft agar. A few hamsters were perfused with glutaraldehyde for studies of tumor ultrastructure. All cloned and uncloned tumor cells were reinoculated to produce second- and third-passage tumors. Characteristic differences in morphology and growth rate were observed between normal astrocytes derived from each brain region, and these phenotypic differences were retained after virus transformation and tumor production. Cloned and uncloned Cx cell-derived tumors of second and third passage diffusely invaded adjacent normal brain, although those of first passage invaded only slightly. Except for extracerebral spread, these tumors resembled human astrocytic series tumors. Bs and some Cbh cell-derived tumors were also astrocytic but more undifferentiated and only slightly invasive; Cbv and other Cbh cell-derived tumors were sarcomatous and only extended along perivascular spaces or were not invasive at all. The tumor cells contained glial fibrillary acidic protein and SV40 T-antigen. These results suggest that astrocytes from different brain regions vary in genomic stability and support the theory that differences in invasiveness reflect the development of heterogeneity and subsequent selection of more aggressive subpopulations of cells.
Animals↗
Neuroimmunomodulation: impairment of humoral immune responsiveness by 6-hydroxydopamine treatment.
Previous studies from this laboratory and others show that perturbations of the central nervous system modulate immune function. In addition, reports from several investigators indicate that depletion of the neurotransmitter norepinephrine (NE) in peripheral nerves by injecting the neurotoxin 6-hydroxydopamine (6-OHDA), can enhance or suppress the antibody response. However, immunocompetence following brain depletion of catecholamines has not been investigated. In this study, we investigated the effects of injecting 6-OHDA into the cisterna magna of male CBA/J mice, and determined the effects of this treatment on both the IgM and IgG antibody responses to sheep red blood cells (SRBC). Both responses are suppressed compared to saline-injected control or normal animals. Animals treated with 6-OHDA have decreased levels of NE in the midbrain, pons-medulla and hypothalamus, while dopamine levels did not change in these brain regions but was decreased in the striatum. The percentage of splenic T cells and B cells was not affected by 6-OHDA treatment. Although there is a marked increase in plasma corticosterone levels in 6-OHDA-treated mice, saline-injected control animals have equivalent increases in plasma corticosterone without concomitant impairment of the immune response. Thus, the decline in immune responsiveness following 6-OHDA treatment does not result from corticosterone-induced immunosuppression. Analysis of the kinetics of the primary IgG response following 6-OHDA treatment indicates that the magnitude, but not the kinetics, of the response decreases. Experiments to determine the effects of 6-OHDA on the afferent and efferent phrases of the response demonstrate that it is effective only when administered prior to immunization, and thus must inhibit early events involved in the initiation of the response. Additional experiments show that mice can be immunized 2 weeks following brain catecholamines depletion and still exhibit a decreased antibody response. However, the response returns to normal levels if immunization is delayed 4 weeks after injection. Further experiments demonstrated that 6-OHDA treatment has no effect on the secondary antibody response, but does inhibit the development of immunological memory. Collectively, these results indicate that 6-OHDA treatment has a profound inhibitory effect on the induction of the primary antibody response and immunological memory development, but is without effect on the secondary antibody response. The data further substantiate the existence of a link between the brain and the immune response.
Animals↗
Brain trace elements in Alzheimer's disease.
Instrumental neutron activation analysis has been used to determine the concentrations of 16 elements in selected brain regions and separated gray- and white-matter specimens from histologically verified Alzheimer's disease (AD) and age-matched control patients. Significantly different (p less than 0.05) mean concentrations of Br, Cl, Cs, Hg, N, Na, P, and Rb were observed in AD bulk brain samples compared to controls, while no significant differences were observed for Ag, Co, Cr, Fe, K, Sb, Sc, and Se. The differences that are most persistent and largest in magnitude for the pooled bulk samples, males and females, left and right hemispheres, and separated gray and white matter are the elevation of Br and Hg and the depletion of Rb in AD compared to controls. Significant interelement correlations for the latter elements in both AD and control brains are also documented. Based on these studies, the possibility of an etiological role for trace elements in AD clearly deserves further investigation.
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Alzheimer's disease: no alteration in the physical state of erythrocyte membrane glycoconjugates.
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Aged↗
Evidence for an increased rate of choline efflux across erythrocyte membranes in Alzheimer's disease.
Alzheimer's disease (AD), the major dementing disorder of the elderly, is associated with cholinergic neuronal loss and decreased activity of choline acetyltransferase (CAT). Previous biophysical studies had suggested an altered conformation of membrane proteins in AD erythrocyte ghosts. Since erythrocytes have a choline transport system and cholinergic neurons are implicated in AD, the present experiments were undertaken to determine if the efflux rate of [14C]choline was altered in AD erythrocytes. The mean efflux rate constant was highly significantly increased (P less than 0.01) by greater than 25% in 9 drug-free AD patients compared to 9 sex-matched, drug-free controls of similar age. These results are discussed in terms of potential molecular mechanisms to account for cholinergic neuronal loss in AD.
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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.
Aging↗
Imaging the centenarian brain. A computed tomographic study.
Ten healthy and mentally alert centenarians underwent cranial computed tomography (CT) using a fourth-generation CT scanner. The subjects ranged in age from 100 to 102 years, and included six women and four men. Two of them used alcohol on a daily basis and five had systolic blood pressures of at least 160 mmHg. The CT scans demonstrated considerable variation in the degree of cerebral atrophy, which had no relation to either sex, alcohol use, or hypertension. Three of the centenarians had evidence of mild periventricular white matter lucency. Although progressive cerebral atrophy is an integral aspect of the normal aging process in the very elderly, its exact relationship to cognitive function remains unclear.
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