Clinically and neuropathologically distinct form of dementia in the elderly.
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Acute Disease↗
Biomedical subjects
E K Perry
Publications and source records attributed to E K Perry.
Comparison of major cortical aminopeptidase activity in normal brain and brain from patients with Alzheimer's disease.
In order to develop a greater understanding of the importance of peptide catabolism in the intracellular protein degradation process in normal and pathological human brain, we have undertaken a systematic investigation of the aminopeptidase group of enzymes. Although a wide range of aminoacyl-7-amino-4-methylcoumarin derivatives (which are used to measure aminopeptidase activity) were hydrolysed by normal human cortical soluble extract, fractionation of the latter via anion exchange and gel filtration chromatography resolved only 4 separable aminopeptidase types (activity relative to alanyl aminopeptidase in parenthesis): alanyl (EC 3.4.11.14, 100%); arginyl (2 isoenzymes, EC 3.4.11.6, 15%); pyroglutamyl (EC 3.4.19.3, 4%); and leucyl (EC 3.4.11.1, 1%). Thus approx. 80% of the total soluble aminopeptidase activity in normal human cerebral cortex can be accounted for by a single enzyme, the major cortical aminopeptidase. The activity of this enzyme was measured in the soluble fraction prepared from 4 cortical regions (occipital, frontal, temporal and parietal) in a series of 8 patients with Alzheimer's disease and compared with corresponding data in 8 control normal patients. Although enzyme activity varied in these cortical regions, the activity in corresponding brain areas in the Alzheimer's disease and normal groups was very similar. These findings suggest that the characteristic neurodegeneration associated with Alzheimer's disease does not result from altered activity of the major cortical aminopeptidase in the cortical tissue of patients with this disorder.
Aged↗
Accuracy of nurses in performing capillary blood glucose monitoring.
The accuracy and outcome of capillary blood glucose (CBG) monitoring as routinely performed by nursing staff were assessed. The sample consisted of 160 readings conducted by 93 nursing staff members in four hospitals; 19% of the readings deviated from simultaneous laboratory results by greater than 20%, and deviations resulted in altered responses to standing orders in 26 patients (17%). There was no statistically significant difference between the total variation attributed within and between nurses, possibly indicating that all nurses should be given the same intensity of follow-up training rather than targeting those who perform incorrectly on sample tests. Nurses in the one hospital that required certification before CBG monitoring had significantly less deviation from the laboratory standard than the other three hospitals. Although these data do not provide direct evidence that the certification program increased accuracy, this seems a logical conclusion. More study is needed to determine the most cost-effective type of training and follow-up.
Blood Chemical Analysis↗
Interaction of 9-amino-1,2,3,4-tetrahydroaminoacridine (THA) with human cortical nicotinic and muscarinic receptor binding in vitro.
Tetrahydroaminoacridine (THA) has recently been reported to be more useful in the treatment of Alzheimer's disease than physostigmine. A comparison of the effects of these two anticholinesterase agents on in vitro enzyme and receptor activities of human cerebral cortex (obtained at autopsy) revealed similarities in their interactions with acetylcholinesterase (AChE) but striking differences in their ability to displace both nicotinic and muscarinic radioligands from membrane preparations. IC50 values (the concentration required to reduce enzyme activity by 50%) for the inhibition of total tissue AChE were 7.9 x 10(-7) M and 4.5 x 10(-8) M for THA and physostigmine, respectively, and similar values were also obtained for individual molecular forms of AChE (monomer G1, dimer G2 and tetramer G4) separated by sucrose density gradient centrifugation. In contrast, IC50 values for [3H]nicotine displacement (a measure of nicotinic cholinergic receptor binding) differed 1000-fold for THA (2 x 10(-5) M) and physostigmine (2 x 10(-2) M) and 100-fold for [3H]N-methylscopolamine displacement (a measure of muscarinic cholinergic receptor binding). Differences were also noted in the inhibition of carbachol stimulated polyphosphoinositide (PI) hydrolysis (a measure of muscarinic receptor induced second messenger activity) in isolated rat cortical miniprisms. It is suggested that variations in clinical efficacy of THA and physostigmine may be related less to their anticholinesterase properties and more to their interactions with other activities such as cholinergic receptors.
Acetylcholinesterase↗
Muscarinic cholinergic receptor subtypes in hippocampus in human cognitive disorders.
Total muscarinic receptor levels, the levels of the subtypes exhibiting high and low affinity for pirenzepine, and the high- and low-affinity agonist states of the receptor were investigated in hippocampal tissue obtained at autopsy from mentally normal individuals and the following pathological groups: Alzheimer's disease, Parkinson's disease, Down's syndrome, alcoholic dementia, Huntington's chorea, and motor-neurone disease. A moderate decrease in the density of both high-affinity pirenzepine and high-affinity agonist subtypes was found in Alzheimer's disease, whereas a trend towards an increase in the overall muscarinic receptor density was apparent in the parkinsonian patients without dementia, mainly due to an increase in the low-affinity agonist state; the differences between the Alzheimer's disease and nondemented parkinsonian cases were highly significant. As previously reported, the levels of both choline acetyltransferase and acetylcholinesterase were markedly reduced in both Alzheimer's disease and Parkinson's disease--with a greater loss of both enzymes in the demented subgroup of parkinsonian patients. Activities of the cholinergic enzymes were also extensively reduced in Down's syndrome, accompanied by a loss of high-affinity pirenzepine binding. There were no significant receptor or enzyme alterations in the other groups studied. These observations suggest that in the human brain, extensive degeneration of cholinergic axons to the hippocampus, as indicated by a loss of cholinergic enzymes, is not necessarily accompanied by extensive muscarinic receptor abnormalities (as might be expected if a major subpopulation were presynaptic). Moreover, the opposite changes in muscarinic binding in Parkinson's and Alzheimer's diseases may be related to the greater severity of dementia in the latter disease.
Acetylcholinesterase↗
Guanine nucleotide modulation of muscarinic cholinergic receptor binding in postmortem human brain--a preliminary study in Alzheimer's disease.
The coupling of cortical muscarinic receptors to guanosine triphosphate (GTP) binding proteins, as defined by changes in agonist affinity states of the receptor in the presence of magnesium ions (Mg2+) and a GTP analogue has been investigated using carbachol in competition experiments with either N-methylscopolamine (NMS) or pirenzepine (PZ). The stability of the system with regard to autopsy delay and freezing was first established in membrane preparations from mouse brain. Applying the same methods to human autopsy tissue from the parietal cortex of Alzheimer's diseased cases and controls, matched for age and postmortem delay, there was no significant difference in the detectable coupling of the total (NMS-labelled) muscarinic receptor population. However, coupling of the 'M1' muscarinic receptor subtype, selectively labelled by PZ, appeared to be more labile than that of the receptor population as a whole and the modulation of this subtype by the GTP analogue was significantly attenuated in Alzheimer's disease.
Aged↗
Loss and recovery of acetylcholinesterase molecular forms in the fornix-lesioned rat hippocampus.
The loss and recovery of hippocampal acetylcholinesterase (AChE) molecular forms was studied following fornix lesions. Two weeks after lesioning, the G4 form, which constituted the majority (91%) of AChE activity in the unlesioned hippocampus, was significantly reduced (P less than 0.01) to levels 21% of those in the unlesioned hippocampus, suggesting that this form is probably presynaptic. Thirteen weeks after lesioning total hippocampal AChE activity had increased 3-fold relative to 2-week animals, with the majority of the recovery in total AChE activity being due to a significant (P less than 0.05) increase in the abundance of the G4 form to levels 340% of those at 2 weeks. The increase in the abundance of the G4 form, which appears to be a functionally important molecular form of AChE within the CNS, serves as a marker of the integrity of the newly formed hippocampal cholinergic synapses.
Acetylcholinesterase↗
Sodium dependent D-[3H]aspartate binding in cerebral cortex in patients with Alzheimer's and Parkinson's diseases.
The sodium dependent binding of D-[3H]aspartate to the high-affinity glutamate uptake system was used as a marker of glutamate-releasing terminals in the cerebral cortex of brains from patients with Alzheimer-type dementia (ATD) and Parkinson's disease (PD). Sodium-dependent D-[3H]aspartate binding was reduced in the ATD patients but not in the PD patients. Within the PD patients no association was observed between sodium-dependent D-[3H]aspartate binding and the presence of dementia. In contrast choline acetyltransferase activity was reduced in both the ATD and the PD patients. The present results suggest that changes in the cortical cholinergic system can occur independently of the cortical glutamate system. The glutamatergic deficit in ATD may contribute to some of the clinical differences between the dementia of ATD and PD.
Aged↗
Molecular forms of butyrylcholinesterase in the human neocortex during development and degeneration of the cortical cholinergic system.
The total levels of butyrylcholinesterase (BChE) activity and, more specifically, the distribution of BChE molecular forms were measured in the human neocortex during fetal development. Both the amount of total activity and the abundance of the different molecular forms (G1 and G4) remained relatively constant between gestational ages of 8-22 weeks and were similar to those observed in samples of cortex from aged brain. In addition, in both Alzheimer-type and parkinsonian dementia, the levels of total BChE activity as well as the relative abundance of the G1 and G4 molecular forms were similar to those observed in control tissue. Hence, both the levels of total activity and the distribution of molecular forms did not change significantly either during fetal development or in the neurodegenerative disorders of Alzheimer-type and parkinsonian dementias. Because these situations are accompanied by changes in the cortical cholinergic system (including an increase and decrease in levels of the G4 form of acetylcholinesterase, respectively), it is concluded that, at least in the human neocortex, BChE is unrelated to cholinergic neurotransmission associated with subcortical cholinergic projection fibres.
Aged↗
Molecular forms of acetylcholinesterase and butyrylcholinesterase in human plasma and cerebrospinal fluid.
The measurement of cholinesterase activities in either plasma or cerebrospinal fluid (CSF) may ultimately prove to be relevant in the diagnosis of neurological and neuropsychiatric disorders. However, studies to date have examined only total enzyme activities. Therefore in the present study we have examined the distribution of the individual molecular forms of both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in plasma and CSF using sucrose density gradient centrifugation. Although the total activities of AChE were of the same order of magnitude in plasma and CSF, there was a considerable difference (120-500-fold) between total BChE activity in the CSF and the BChE-rich plasma. The analysis of the individual molecular forms revealed that the predominant molecular species of AChE and BChE in the CSF--both lumbar and ventricular--was the G4 form. The G4 form also constituted the majority of the plasma BChE activity and, on average, over half (56%) of the plasma AChE activity. The significance of the AChE and BChE molecular form compositions of both plasma and CSF and their possible relationship to pathological states are discussed.
Acetylcholinesterase↗
Recovery and measurement of RNA in Alzheimer's disease by molecular hybridisation.
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Alzheimer Disease↗
Nicotinic receptor abnormalities in Alzheimer's and Parkinson's diseases.
The status of cholinergic receptors in dementia is related to the question of potential cholinergic therapy. Whilst muscarinic receptor binding is generally reported to be normal or near normal, findings are reported which indicate substantial reductions of hippocampal nicotinic (high affinity nicotine) binding (occurring in conjunction with decreased choline acetyltransferase) in both Alzheimer's and Parkinson's but not Huntington's disease. A further indication that nicotinic receptor function may be abnormal in Alzheimer's disease is the extensive loss of an endogenous compound, detected for the first time in human brain, which inhibits normal nicotinic binding. Both receptor binding and the inhibitor are also substantially decreased with increasing age in the normal hippocampus.
Adult↗
Cortical neuropathological and neurochemical substrates of Alzheimer's and Parkinson's diseases.
Whilst the neuropathological correlates of Alzheimer type dementia--cortical neurofibrillary tangles and senile plaques--are well defined, the prevalence of these cortical abnormalities in Parkinson's disease and their relation to dementia is unclear. In a series of 46 consecutive cases of clinically and pathologically established Parkinson's disease the prevalence of mild Alzheimer-type pathology (exceeding the normal but not as extensive as in Alzheimer's disease) was increased 2 to 3 fold compared with an age-matched control group, although there was no obvious relation to the presence or severity of dementia. In a subgroup of Parkinsonian cases (both demented and non-demented), examined neurochemically, there were both similarities (decreased choline acetyltransferase, nicotinic and serotonergic S 1 receptor activities) and distinctions (increased muscarinic receptor binding--particularly to the "L" subtype, and normal serotonergic S 2, somatostatin, and D-aspartate binding together with normal levels of an endogenous nicotine binding inhibitor) compared with a group of cases with Alzheimer's disease. Amongst the various pathological and chemical indices examined, only presynaptic cholinergic markers (including the number of Meynert neurons) and S 1 receptor binding were related to dementia in Parkinson's disease. It is suggested that whilst coincidental classical Alzheimer's disease is infrequent in Parkinson's disease (5% in the present series) Alzheimer's disease itself is distinguished from Parkinson's disease by the formation of numerous neocortical neurofibrillary tangles and a reduction in glutamate uptake, serotonergic S 2 receptors and possibly in endogenous nicotine binding inhibitor.
Adult↗
Aluminosilicates and senile plaque formation in Alzheimer's disease.
Aluminium and silicon were found to be colocalised in the central region of senile plaque cores in studies with energy dispersive X-ray microanalysis. The distribution of these elements was similar in cores isolated from the cerebral cortex of patients with senile dementia of the Alzheimer type and in cores studied in situ from tissue sections from the cerebral cortex of presenile and senile patients with Alzheimer's disease, and elderly, mentally normal patients. High-resolution solid-state nuclear magnetic resonance techniques showed aluminium and silicon to be present as aluminosilicates. The presence of aluminosilicates at the centre of senile plaque cores contrasts with the distribution of other inorganic constituents and suggests that they may be involved in the initiation or early stages of senile plaque formation.
Aged↗
Recovery and measurement of specific RNA species from postmortem brain tissue: a general reduction in Alzheimer's disease detected by molecular hybridization.
The recovery of RNA from postmortem (PM) brain tissues was quantified by molecular hybridization. RNA degradation rates postmortem were faster in mice with herpes encephalitis than with uninfected mice, but clear ribosomal peaks could be seen up to 72 hr after death. In a comparison between frontal cortex samples from neurologically normal and Alzheimer's disease cases a reduction in ribosomal, poly A, preproenkephalin, and preprosomatostatin RNA levels was observed in the Alzheimer's disease group. This general reduction may be influenced by the cause of death as well as the pathology.
Alzheimer Disease↗
The current status of the cortical cholinergic system in Alzheimer's disease and Parkinson's disease.
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Acetylcholinesterase↗
Cholinergic receptors in cognitive disorders.
Cholinergic receptors (muscarinic subtypes M1 and M2, and putative nicotinic binding) have been examined in the hippocampus obtained at autopsy from a variety of patients with cognitive disorders (Alzheimer's, Parkinson's, and Huntington's diseases, Down's Syndrome and alcoholic dementia) and compared with neurologically normal controls and cases of Motor Neuron disease. In all of the disorders associated with a pre-synaptic cortical cholinergic deficit reflected by an extensive loss of choline acetyltransferase (Alzheimer's disease, Parkinson's disease and Down's Syndrome) there was a substantial reduction in the binding of (3H) nicotine to the nicotinic receptor. By contrast reductions in both muscarinic subtypes (M1 and M2) were apparent to only a moderate extent in Alzheimer's disease, whereas in Parkinson's disease binding was significantly increased (apparently not in relation to anti-cholinergic drug treatment) in the non-demented but not demented cases. A further abnormality detected in Alzheimer's disease but not the other disorders investigated was a decrease in an endogenous inhibitor of nicotinic binding, the identity of which is as yet unknown but which may be a candidate for a possible endogenous modulator of the nicotinic receptor. These observations suggest that in Alzheimer's disease not only muscarinic but also nicotinic receptor function should be considered in relation both to future therapeutic strategies and, in the search for a clinical marker which might be of diagnostic value, to potential probes of the cortical cholinergic system.
Cognition Disorders↗
The cholinergic hypothesis--ten years on.
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Acetylcholine↗