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E K Perry

Publications and source records attributed to E K Perry.

At least 109 records · Page 6Linked to original sources

Nicotine reduces the binding of [3H]MK-801 to brain membranes, but not via the stimulation of high-affinity nicotinic receptors.

Nicotine (10 and 100 microM) inhibited [3H]MK-801 binding to rat cerebral cortical membranes and this effect was not blocked by dihydro-beta-erythroidine, (+)-tubocurarine or mecamylamine. Cytisine, muscarine mecamylamine and (+)-tubocurarine also inhibited [3H]MK-801 binding. Neither raising the MK-801 concentration, nor the addition of n-methyl-D-aspartate (NMDA) receptor agonists altered the effects of nicotine. Hence this response is not mediated via high-affinity nicotinic receptor stimulation, competition for MK-801 binding sites or require NMDA receptor activation.

Animals↗

Biochemical assay of Alzheimer's disease--associated protein(s) in human brain tissue. A clinical study.

The concentration of Alzheimer's disease-associated protein (ADAP) was measured in postmortem brain tissue samples of temporal or frontal cortex from 111 human brains using a sandwich immunoassay. Alzheimer's disease-associated protein has three major ALZ-50-reactive subunits, including A-68. This assay utilizes ALZ-50 and a rabbit antibody raised against a highly ADAP-enriched brain protein fraction. The frequently observed cross-reactivity of ALZ-50 with normal brain components in direct immunoassays is minimized by this configuration. There were 27 normal controls, 28 neurologic disease controls, and 56 Alzheimer's disease cases. The normal control and neurologic disease control cases had essentially no detectable level of ADAP, while ADAP was clearly detected in 85.7% of the Alzheimer's disease cases. Clinical dementia, neuritic plaques, and old age per se are not correlated with increased ADAP levels. This biochemical assay of ADAP may prove to be helpful as an adjunct in the clinicopathologic diagnosis of Alzheimer's disease.

Aged↗

Cholinergic nicotinic and muscarinic receptors in dementia of Alzheimer, Parkinson and Lewy body types.

Cholinergic nicotinic and muscarinic receptor binding were measured in post mortem human brain tissue, using low (nM) concentrations of (3H)-nicotine to detect predominately the high affinity nicotinic site and (3H)-N-methylscopolamine in the presence and absence of 3 x 10(-4) M carbachol to measure both the low and high affinity agonist subtypes of the muscarinic receptor group. Consistent with most previous reports, the nicotinic but not muscarinic binding was reduced in the different forms of dementia associated with cortical cholinergic deficits, including Alzheimer's and Parkinson's disease, senile dementia of Lewy body type (SDLT) and Down's syndrome (over 50 years). Analysis of (3H)-nicotine binding displaced by a range of carbachol concentrations (10(-9)-10(-3) M) indicated 2 binding sites for nicotine and that the high affinity rather than low affinity site was reduced in Alzheimer's disease. In all 3 cortical areas investigated (temporal, parietal and occipital) there were increases in the low affinity muscarinic site in Parkinson's disease and SDLT but not Alzheimer's disease or middle-aged Down's syndrome. This observation raised the question of whether the presence of neurofibrillary tangles (evident in the latter but not former 2 disorders) is incompatible with denervation-induced muscarinic supersensitivity in cholinoceptive neurons which include cortical pyramids generally affeted by tangle formation.

Adult↗

Parameters of cholinergic neurotransmission in the thalamus in Parkinson's disease and Alzheimer's disease.

Loss of cholinergic cells in the basal forebrain is associated with commensurate reductions in cortical acetylcholine-related enzyme activities in both Alzheimer's disease (AD) and Parkinson's disease (PD). Nerve cell loss from the cholinergic pontine tegmental nuclei also occurs. As the latter nuclei project to the diencephalon, we used frozen tissue from 5 controls, 5 PD and 5 AD cases to study the distribution of ChAT, AChE and [3H]nicotine binding in the thalamus and subthalamic nucleus. The anterior nuclear group and the mediodorsal nucleus showed high activities of ChAT and AChE together with relatively high levels of [3H]nicotine binding. The centromedian nucleus and subthalamic nucleus contained equally high levels of ChAT but negligible levels of [3H]nicotine binding. There were no significant changes in the levels of ChAT, AChE and nicotine binding in the PD and AD groups indicating that involvement of the pedunculopontine tegmental nucleus is likely to be a secondary retrograde phenomenon rather than part of a systematic cholinergic fibre degeneration.

Acetylcholine↗

Comparison of aminopeptidase, dipeptidyl aminopeptidase and tripeptidyl aminopeptidase activities in brain tissue from normal and Alzheimer's disease cases.

Recent evidence has suggested that Alzheimer's disease may result from an underlying defect of protein catabolism. In an attempt to identify such a defect, we have undertaken the systematic identification and characterization of the proteolytic enzymes responsible in human brain for oligopeptide breakdown via hydrolysis of NH2-terminal residues--the aminopeptidases, dipeptidyl aminopeptidases and tripeptidyl aminopeptidases. The activities of these enzymes were determined following anion exchange chromatographic fractionation of cortical soluble extracts, to prevent interference in the respective assay procedures by the major cortical aminopeptidase. Corresponding enzyme types showed similar levels of activity in soluble extracts of frontal cortex from normal and Alzheimer's disease cases. These data suggest that the characteristic neurodegeneration associated with Alzheimer's disease does not result from altered aminopeptidase, dipeptidyl aminopeptidase or tripeptidyl aminopeptidase activity in cortical tissues of patients with this disorder.

Aged↗

Senile dementia of Lewy body type. A clinically and neuropathologically distinct form of Lewy body dementia in the elderly.

A dementing syndrome has been identified in a group of psychiatric cases aged 71-90 years, presenting initially with a subacute/acute confusional state, often fluctuating and associated with visual hallucinations and behavioural disturbances. Clinically, these cases did not meet criteria for a diagnosis of Alzheimer's disease, and many were assigned to the multiinfarct dementia group, although no significant ischaemic lesions were evident at autopsy. Mild extrapyramidal features were apparent in a number of cases but the characteristic clinical triad of Parkinson's disease, i.e., tremor, rigidity, and akinesia, was absent. Detailed neuropathological examination revealed Lewy body formation and selective neuronal loss in brain stem and other subcortical nuclei, accompanied by Lewy body formation in neo- and limbic cortex, at densities well below those previously reported in diffuse Lewy body disease. A variable degree of senile degenerative change was present; numerous senile plaques and minimal neurofibrillary tangles in most cases. Neither the clinical nor the neuropathological features of this group are typical of Parkinson's or Alzheimer's disease, but suggest a distinct neurodegenerative disorder, part of the Lewy body disease spectrum, in which mental symptoms predominate over motor disabilities and lead to eventual psychogeriatric hospital admission. In a sequential series of autopsies conducted on clinically assessed demented patients, neuropathological analysis has indicated that such cases may comprise up to 20% of a hospitalized population of demented old people over the age of 70 years, an observation clearly relevant to the diagnosis and management of dementia in the elderly.

Aged↗

Memory following cholinergic (NBM) and noradrenergic (DNAB) lesions made singly or in combination: potentiation of disruption by scopolamine.

Groups of rats were trained on either delayed matching or nonmatching to position tasks, then divided into four subgroups and given the following bilateral lesions: (a) SHAM [vehicle injection into the nucleus basalis magnocellularis (NBM) and dorsal noradrenergic bundle (DNAB)], (b) DNAB (6-hydroxydopamine lesion of the DNAB, vehicle into the NBM), (c) NBM (quisqualic acid lesion of the NBM, vehicle into the DNAB) and (d) DUAL (neurotoxin lesions of both DNAB and NBM). Following postoperative recovery, the DUAL lesion subjects were slightly impaired, but by the seventh day of testing all groups were performing at similar levels. This strongly suggests that quisqualate lesions of the NBM are not sufficient to produce severe and lasting mnemonic disorders resembling those seen in Alzheimer's disease (AD). These data also indicate that the noradrenergic system may not be of critical importance with respect to cognition. It was reasoned that an additional anticholinergic treatment might exacerbate an underlying deficiency. All groups were injected, peripherally, with the cholinergic antagonist scopolamine (0-0.5 mg/kg). This drug dose-dependently disrupted performance in all groups. Moreover, the highest dose had a marked effect in the DUAL group, impairing performance even when no mnemonic burden was present (at zero delay). The results suggest that cholinergic NBM and noradrenergic DNAB lesions produce only transient mnemonic deficiencies. A combination of the two can be disruptive, but longer term task (or reference) memory is the primary process affected, and only under certain conditions. The implication of these findings to research concerning animal models relating to Alzheimer's disease is discussed.

Animals↗

Nerve growth factor and the basal forebrain cholinergic system: a link in the etiopathology of neurodegenerative dementias?

The discovery of a specific association between nerve growth factor (NGF) and basal forebrain cholinergic neurons (BFCNs) marks the beginning of a new era of research into neurodegenerative diseases such as Alzheimer disease (AD). Degeneration of BFCNs appears to be one of the earliest and most prominent neuropathological features of a broad range of diseases of the human brain that give rise to loss of memory and dementia (including, in addition to Alzheimer disease, Parkinson disease, Lewy body dementia, progressive supranuclear palsy, dementia pugilistica, olivopontocerebellar atrophy, and Wernicke-Korsakoff syndrome). Selective localization of NGF receptors on BFCN, the relatively high levels of NGF mRNA in BFCN target areas, and numerous effects of exogenous NGF in vivo and in vitro provide overwhelming evidence that the structure and function of BFCNs in the adult brain are dependent on this molecule. The question then arises as to how this special relationship is disturbed in the diseased human brain? Initial investigations in AD have already indicated a normality of NGF mRNA and retention of receptors in the basal forebrain region. Interpretation of these results and the therapeutic relevance of NGF obviously depend upon future developments in understanding the role of NGF in the normal and pathological brain.

Alzheimer Disease↗

Distribution of neurofibrillary tangle formation and [3H]-D-aspartate receptor binding in the thalamus in the normal elderly brain, in Alzheimer's disease and in Parkinson's disease.

The overactivity of glutamatergic neurons may underlie some neurodegenerative disorders, including Alzheimer's disease (AD). We explored the relationship between glutamatergic transmission and neurofibrillary tangle formation by measuring [3H]-D-aspartate binding activity and the proportion of neurons containing tangles within individual thalamic nuclei in five AD cases. Five elderly normal and five Parkinson's disease (PD) cases were used as controls. A highly significant correlation between [3H]-D-aspartate binding and tangle counts in Alzheimer's disease suggests that those thalamic nuclei which normally receive a relatively dense glutamatergic afferent input are predisposed to tangle formation. There were no significant differences in individual thalamic nuclear [3H]-D-aspartate binding between controls and the AD and PD groups.

Aged↗

Evidence of a monoaminergic-cholinergic imbalance related to visual hallucinations in Lewy body dementia.

Senile dementia of Lewy body type is characterized clinically by a relatively acute onset of fluctuating memory loss and confusion, frequently accompanied by visual hallucinations. Neurochemical analyses of temporal cortex has revealed a distinction between hallucinating and nonhallucinating patients in both cholinergic and monaminergic transmitter activities. In contrast with the cholinergic enzyme choline acetyltransferase, which was more extensively reduced in hallucinating individuals, serotonergic S2 receptor binding and both dopamine and serotonin metabolites were significantly decreased in nonhallucinating cases. These results suggest that an imbalance between monaminergic and cholinergic transmitters is involved in hallucinogenesis in the human brain.

Acetylcholine↗

Cholinergic and dopaminergic activities in senile dementia of Lewy body type.

Analyses of brain tissue in a recently identified group of elderly demented patients suggest a neurochemical basis for some of the clinical features. Senile dementia of the Lewy body type (SDLT) can be distinguished from classical Alzheimer disease (AD) clinically by its acute presentation with confusion frequently accompanied by visual hallucinations, and neuropathologically by the presence of Lewy bodies and senile plaques (but not generally neurofibrillary tangles) in the cerebral cortex. Reductions in the cortical cholinergic enzyme choline acetyltransferase were more pronounced in individuals with (80%) compared to those without (50%) hallucinations and correlated strongly with mental test scores in the group as a whole. In the caudate nucleus, dopamine levels were related to the number of neurons in the substantia nigra, there being a 40-60% loss of both in SDLT--probably accounting for mild extrapyramidal features in some of these cases--compared with an 80% loss in Parkinson disease and no change in AD. The cholinergic correlates of mental impairment in SDLT together with the relative absence of cortical neurofibrillary tangles and evidence for postsynaptic cholinergic receptor compensation raise the question of whether this type of dementia may be more amenable to cholinotherapy than classical AD.

Aged↗

Distribution of [3H]MK801 binding in the normal aged human hippocampus.

The distribution of NMDA receptors in the normal human hippocampus has been investigated using the non-competitive channel blocking agent, MK801. The pattern of specific [3H]MK801 binding was broadly similar to that previously described for agonist binding although differences included equal densities in h1 and h2 regions where binding was mainly confined to the pyramidal layer and stratum radiatum.

Aged↗

Increases in muscarinic stimulated hydrolysis of inositol phospholipids in rat hippocampus following cholinergic deafferentation are not parallelled by alterations in cholinergic receptor density.

The effect of electrolytic fimbria/fornix lesions on muscarinic receptor subtypes and putative nicotinic binding sites in the hippocampus has been studied using [3H]N-methylscopolamine, [3H]pirenzepine and [3H]L-nicotine, respectively. In parallel experiments the carbachol-stimulated hydrolysis of inositol phospholipids was measured after incorporation of [3H]inositol into hippocampal slice preparations. Ten days after lesioning there were no apparent changes in either receptor density or affinities despite extensive reductions in choline acetyltransferase. In contrast a significant increase in carbachol stimulated turnover of inositol phospholipids was measured. These observations suggest that whilst loss of cholinergic afferents may not affect receptor density per se, the efficacy of the post synaptic muscarinic receptors can be up-regulated at least in the short term.

Animals↗