Circadian variation in human brain enzymes.
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Acetylcholinesterase↗
Biomedical subjects
E K Perry
Publications and source records attributed to E K Perry.
Necropsy evidence of central cholinergic deficits in senile dementia.
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Acetyltransferases↗
Human brain temperature at necropsy: a guide in post-mortem biochemistry.
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Animals↗
Neurotransmitter enzyme abnormalities in senile dementia. Choline acetyltransferase and glutamic acid decarboxylase activities in necropsy brain tissue.
Reductions in 2 neurotransmitter synthesizing enzymes in brain, glutamic acid decarboxylase (GAD) and choline acetyltransferase (CAT), have been found in dementias of different origins, including senile dementia (Alzheimer type). Significant reductions in cerebral GAD have also been found in depression (unipolar). The GAD reductions did not generally appear to be localised in any specific region of the brain examined. However, the reduction of CAT in the hippocampus, relative to reductions in other areas examined, was substantially greater in the brains with Alzheimer-type changes. GAD and CAT activities in normal brains were examined for the effects of some variable factors inherent in necropsy biochemical measurements. These factors included: (i) age; (ii) agonal status; (iii) time of death, and (iv) delay in tissue sampling; and GAD was found to be significantly influenced by (ii), (iii) and (iv) and CAT by (i), (iii) and (iv). None of these factors accounted for the total alterations in the enzyme activities of the mentally abnormal brains. The results indicate that reductions in cerebral GAD require to be interpreted with caution in view of the sensitivity of this enzyme to premortem status but that reductions in cerebral CAT may be a more reliable index of pathological change in senile (Alzheimer-type) dementia.
Age Factors↗
Evidence of a circadian fluctuation in neurotransmitter enzyme activities measured in autopsy human brain.
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Acetyltransferases↗
Monoamine metabolism in senile dementia of Alzheimer type.
Monoamine metabolism in senile dementia of the Alzheimer-type (SDAT) was assessed by measuring the concentrations of the dopamine metabolite HVA, the noradrenaline metabolite MHPG and serotonin metabolite 5-hydroxy-3-indoleacetic acid (5-HIAA) in post-mortem brains of SDAT patients, a group of control subjects and a group of chronically depressed patients. Concentrations of MHPG and 5-HIAA were significantly reduced in hippocampus and cortical regions of the SDAT group. These changes did not correlate with clinical assessments of the degree of dementia or neuropathological assessment of the degree of Alzheimer-type changes in the SDAT group. It is suggested that changes in monoamine metabolite concentrations are not primarily involved in the pathogenesis of SDAT, and may be secondary to the well established cholinergic deficits.
Aged↗
5-HT receptor binding in post-mortem brain from patients with affective disorder.
Post-mortem brain tissue was obtained from a group of patients with well documented clinical histories of affective disorder. 5-Hydroxytryptamine-1 (5-HT1) and 5-HT2 receptor binding to homogenates of frontal cortex (Brodmann area 10) was measured using tritiated 5-HT and tritiated ketanserin respectively. 5-Hydroxyindoleacetic acid (5-HIAA) levels from the same brain samples were measured by reverse-phase high performance liquid chromatography with electrochemical detection. A tendency towards increased 5-HT receptor binding density in patients with major affective disorder was found compared to dysthymic disorder patients and normal controls. No relationship was found between receptor binding densities and metabolite values, nor were the differences in 5-HT binding correlated with time to autopsy, storage time prior to assay, or to clinical variables including DSM-III psychoticism/non-psychoticism and melancholia. Previous antidepressant drug histories were similar in the two patient groups and are unlikely to account for the findings. An increase in postsynaptic 5-HT2 receptor binding in major affective disorder is a possible pathophysiological mechanism which is compatible with the observed down-regulatory effect of antidepressant drugs (although not electroconvulsive therapy) on 5-HT2 sites. The methodological problems inherent in post-mortem studies in affective disorder are discussed.
Aged↗
Amyloid and Alzheimer's disease: a question of specificity.
As with potential neurotransmitter therapy, the question of how successful reducing amyloid deposits would be in the treatment of Alzheimer's disease hinges on the position of amyloid formation in the pathological cascade. Identification of the presence of A4 reactive plaques and neurofibrillary tangles, either separately or together, in an increasingly wide variety of distinct diseases strongly suggests amyloid formation is "downline" in a variety of pathological processes. Thus, there may be no reason to expect amyloid therapy to be more effective than, say, transmitter therapy and, in view of the fact that neurodegeneration probably occurs in conjunction with amyloid formation, both therapeutic approaches should perhaps be considered together until such time as the primary etiopathological event is identified.
Alzheimer Disease↗
Convergent cholinergic activities in aging and Alzheimer's disease.
Choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activities have been examined postmortem in a series of 66 individuals with no evidence of CNS disease, ranging in age from 24 gestational weeks to 95 years and in 33 cases of Alzheimer's disease (AD) aged 57-89 years. In the normal human hippocampus a striking and highly significant age-related decline in ChAT occurred from middle to old age (between 40 and 100 years); a trend apparent at a later stage and to a lesser extent in the hippocampal gyrus. In both areas enzyme activity in AD was inversely related to age at death; reductions compared with the normal were on average 70-80% in the 60-70 year old groups compared with 30-40% in the 80-90 year old group. A similar trend was apparent with respect to acetylcholinesterase (AchE) histochemical activity associated with fibers and terminals (predominantly cholinergic and concentrated in CA3 and 4 of the hippocampus) but not with reactive perikarya (considered to be noncholinergic) present in both hippocampus and cortex. These data indicate that the normal aging human hippocampus may constitute a useful model for investigating the dysfunction or degeneration of basal forebrain cholinergic neurons in AD.
Acetylcholinesterase↗
Glutamate receptor binding in the human hippocampus and adjacent cortex during development and aging.
Distinct patterns of age-related alterations in NMDA (MK801 binding) and non-NMDA, AMPA (CNQX), and kainate binding have been identified in human hippocampus and parahippocampal gyrus in normal individuals with no evidence of degenerative brain disease ranging in age from 24 gestational weeks to 94 years. Whereas MK801 binding did not alter substantially over this age range, CNQX binding rose from low levels in the fetus to maximum levels between neonate and middle age, and kainate binding declined extensively from the perinatal to adult stage. Following maturity, there were no significant changes in kainate binding, although MK801 binding increased in CA1 and CA3 and CNQX binding declined in several regions, particularly CA2 and subiculum. For each receptor binding the timing of these fluctuations ocurring during development and aging varied within different regions of the dentate gyrus, hippocampus proper, subicular complex, and entorhinal cortex examined. The transient peaks of receptor binding are likely to reflect processes of synaptogenesis and pruning and may provide clues regarding the role of the different glutamate receptor subtypes in various pathologies of the hippocampus and adjacent cortex associated with developmental disorders (of genetic origin or due to perinatal trauma or insult). The absence of substantial changes in any subtype examined from middle to old age suggests alterations in transmitter binding to these glutamate receptors are not involved in senescent neurodegeneration.
Adolescent↗
Autoradiographic distribution of [3H]nicotine binding in human cortex: relative abundance in subicular complex.
Distinct patterns of [3H]nicotine (3 nM) binding were apparent in various regions of adult human neo- and archicortex. Receptor binding was greatest in the subicular complex--particularly presubiculum--and entorhinal cortex, where it was prominent in the characteristic parvo- and magnocellular islands of these regions and in middle layers of entorhinal cortex. In somatosensory cortex (Brodmann areas 3, 1 and 2) and occipital (area 17) cortex binding was highest in the upper and lower layers, and relatively sparse in the sensory input, layer IV. In primary motor (area 4) and temporal (area 21) cortex, binding in the outer half of the cortical ribbon was denser than that in the inner half and a distinct band was apparent in temporal and cingulate (area 32) in the lower portion of layer III. In prefrontal association cortex the pattern of binding was less distinct although slightly higher in the lower architectonic layers. There was generally little binding in the hippocampus (areas CA1-4) and dentate gyrus with the exception of the stratum lacunosum moleculare in CA2-3 and, to a lesser extent, supra- and subgranule zones of the dentate. These patterns of reactivity, which are distinct from that of the major cortical cholinergic innervation, suggest that the nicotinic receptor, detected using nanomolar concentrations of [3H]nicotine, may primarily be associated with intracortical circuitry in the neocortex. The relatively high density in entorhinal and subicular regions may be related to the extensive phylogenetic development of these regions which has occurred in conjunction with the development of multimodal association circuitry in the human cortex.
Adolescent↗
Changes in brain cholinesterases in senile dementia of Alzheimer type.
Acetyl- and butyryl-cholinesterase activities have been measured biochemically in normal brain tissue, in senile dementia of Alzheimer type and in mental disorders without Alzheimer-type abnormalities. Acetylcholinesterase was significantly reduced and butyrylcholinesterase significantly increased, compared with the normal, in the hippocampus and temporal cortex of the Alzheimer cases. No significant enzyme changes were seen in the other diseases investigated including multi-infarct dementia, schizophrenia and depression. There was no correlation between age and acetylcholinesterase activity, but a significant positive correlation between the butyrylcholinesterase activities with increasing age (60-90 years) was found in the hippocampus. The possible connection between cholinergic system pathology and these cholinesterase abnormalities in Alzheimer dementia is discussed.
Acetylcholinesterase↗
Quantification and characterization of fluctuating cognition in dementia with Lewy bodies and Alzheimer's disease.
Fluctuating cognition (FC) is a common and important symptom in dementia, particularly dementia with Lewy bodies (DLB), although it has not been empirically quantified or characterised. Forty subjects (15 DLB, 15 AD, 10 elderly controls) were evaluated using a clinical FC severity scale, as well as receiving measures of variability in attentional performance and slow EEG rhythms across 90 s, 1 h and 1 week. DLB patients had significantly more severe FC and more severe variability in attentional and slow electrocortical measures than either AD patients or normal controls in all time frames. Attentional and EEG variability also correlated significantly with independent clinical ratings of FC. Clinical quantification and measures of attention and EEG variability can therefore make an important and standardised contribution to the assessment of FC in dementia, facilitating future treatment studies with important implications for the potential causative mechanisms and differential diagnosis.
Aged↗
Senile dementia of Lewy body type and Alzheimer type are biochemically distinct in terms of paired helical filaments and hyperphosphorylated tau protein.
We have used biochemical assays to examine cingulate and occipital cortices from age-matched cases of Alzheimer's disease (AD; n = 12), senile dementia of the Lewy body type (SDLT; n = 13), Parkinson's disease (PD; 5 non-demented cases and 7 cognitively impaired cases) and controls (n = 11) for paired helical filaments (PHFs), phosphorylated and normal tau protein and beta/A4-protein. Whereas cingulate cortex is characterised by relatively high densities of cortical Lewy bodies in the SDLT cases and lower numbers in PD, these inclusion bodies were absent in the cingulate cortex from AD and control cases. Protease-resistant PHFs and hyperphosphorylated tau protein were found in AD and, at low levels, in a minority of SDLT cases. Qualitatively, both of these preparations were indistinguishable in SDLT from those found in AD but levels of both parameters in SDLT were less than 5% of those in AD. SDLT, PD and control groups did not differ from each other in terms of the quantity of protease-resistant PHFs or the level of hyperphosphorylated tau. Furthermore, PHF accumulation did not distinguish between PD cases with or without dementia. The levels of normal tau protein did not differ between the four groups. beta/A4 protein levels did not distinguish between PD and control groups, between AD and SDLT groups, or between SDLT and control groups for either cingulate or occipital cortices. Thus extensive accumulation of PHFs in either neurofibrillary tangles or dystrophic neurites is not a feature of either SDLT or PD. Our findings provide molecular support for the neuropathological and clinical separation of SDLT as a form of dementia that is distinct from AD.
Aged↗
Regional distribution of muscarinic and nicotinic cholinergic receptor binding activities in the human brain.
The distribution of nicotinic and muscarinic receptor subtypes was examined in human brain tissue obtained at autopsy from neurologically normal adult (50-60 years) individuals. Membrane preparations from 15 brain regions were examined for nicotinic (L-[3H]nicotine) binding, both M1 and M2 muscarinic receptor binding (distinguished on the basis of pirenzepine affinity) and high (H) and low (L) affinity muscarinic agonist binding (distinguished on the basis of carbachol displacement). Total muscarinic receptor binding sites were relatively high in striatal and cortical areas, where both M1 subtype and agonist binding type L predominated, compared with thalamic, nigral and cerebellar regions and spinal cord, where the M2 subtype and agonist binding type H predominated. Nicotinic receptor binding sites (predominantly high affinity, measured at low ligand concentrations) did not parallel any of the muscarinic subtypes, being concentrated in thalamic, neocortical and striatal regions. Scatchard analysis indicated the presence of both high and low affinity nicotinic sites, the numbers of the latter generally exceeding the former by over one order of magnitude. Neither muscarinic nor nicotinic receptor binding sites were closely related to the distribution of the cholinergic neuronal marker, choline acetyltransferase, suggesting that individual cholinergic pathways may be distinguished by the relative proportion of the different types of cholinergic receptors present.
Binding, Competitive↗