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Biomedical subjects

E K Perry

Publications and source records attributed to E K Perry.

At least 91 records · Page 5Linked to original sources
PubMed1992

Hippocampal nerve growth factor receptor immunoreactivity in patients with Alzheimer's and Parkinson's disease.

Using the monoclonal antibody, ME 20.4, against the p75 nerve growth factor (NGF) receptor, NGF receptor-like immunoreactivity has been identified in axonal processes innervating the human hippocampus, where previously a loss of reactivity has been reported in a preliminary study of Alzheimer's disease [10]. In an extended analysis of 15 cases of Alzheimer's disease, the number of NGF receptor positive fibres in the fimbria and alveus was generally decreased compared with age-matched normal groups, in presenile but not senile cases (differentiated by age of onset before or after 65 years). By contrast, in 5 demented Parkinson's disease cases (aged 61-86 years at death) immunohistochemically reactive fibres were consistently minimal or absent. This pattern of NGF receptor loss in the hippocampus most closely reflects the loss of basal forebrain cholinergic neurones, previously reported within the different clinical groups but not by biochemical measures of cholinergic function. It is concluded that even at moderately advanced stages of Alzheimer's disease with onset in the senium, axonal processes and NGF receptor mechanisms may be structurally intact in areas of cholinergic innervation from the basal forebrain, despite evidence of cholinergic dysfunction (decreased choline acetyltransferase (ChAT) and acetylcholinesterase), but that in presenile Alzheimer's and in demented Parkinson's disease cases the receptor declines in conjunction with the loss of subcortical neurones and their processes. The loss of ChAT activity may therefore reflect a dysfunction of the NGF system, in its normal maintenance of the cholinergic phenotype in basal forebrain neurones.

Adult↗
PubMed1992

[3H]MK-801 binding to the NMDA receptor complex, and its modulation in human frontal cortex during development and aging.

[3H]MK-801 binding was found to decline with age in well washed membranes from human frontal cortex taken from an age series from 24 weeks gestation to 100 years old. The decline was significant under basal conditions (no added modulators) (P less than 0.01), and highly significant under stimulation with glutamate, glycine and spermidine alone and in combination (P less than 0.001). Scatchard analysis in the presence of glutamate and glycine showed this decline was due to a loss in the number of [3H]MK-801 binding sites rather than a change in the affinity of the binding site. There was a highly significant age related reduction in the attenuation of [3H]MK-801 binding by zinc (P less than 0.001). In foetal and neonatal cases up to 7 weeks of age spermidine behaved in an antagonistic manner, inhibiting rather than stimulating [3H]MK-801 binding, when alone or in the presence of glutamate and glycine. The changes in influence of glutamate, glycine, spermidine and zinc on [3H]MK-801 binding during development and aging were not due to other pre- or postmortem factors. The reverse effect of spermidine in the foetal and neonatal cases has therapeutic implications in the treatment of neonates with antiischaemic agents whose action involves the polyamine site.

Adolescent↗
PubMed1992

The quantitative autoradiographic distribution of [3H]MK-801 binding sites in the normal human brainstem in relation to motor neuron disease.

The distribution of N-methyl-D-aspartate (NMDA) receptors in the normal human brainstem has been investigated using MK-801. Specific [3H]MK-801 binding showed a heterogeneous distribution, the greatest density of binding sites being found in the substantia nigra, locus coeruleus, and the hypoglossal and inferior olivary nuclei. Brainstem motor nuclei subserving eye movements, which tend to be spared in motor neuron disease (MND), had significantly lower densities of binding compared to other cranial nerve motor nuclei (V, VII, X, XII) which tend to be affected. The anatomical distribution of NMDA receptors may be one factor determining selective vulnerability to excitotoxic injury.

Adult↗
PubMed1992

Operational criteria for senile dementia of Lewy body type (SDLT).

Recent reports have suggested that brain stem and cortical Lewy body formation may identify a neurodegenerative disorder in elderly demented individuals which accounts for up to 20% of cases of senile dementia coming to autopsy. Retrospective analysis of case notes of 21 autopsy patients with neuropathologically proven senile dementia of Lewy body type (SDLT) and 37 cases with neuropathologically proven Alzheimer's disease (AD) identified a characteristic clinical syndrome in SDLT. Fluctuating cognitive impairment; psychotic features including visual and auditory hallucinations, and paranoid delusions; depressive symptoms; falling and unexplained losses of consciousness were all seen significantly more often than in AD. Over half of the SDLT patients in this series who were given neuroleptics in standard dose showed acute and often irreversible adverse reactions indicative of a neuroleptic sensitivity syndrome. The survival time of drug treated patients was reduced by 50%. Operational criteria to aid in the clinical distinction between SDLT and AD patients are proposed and hypotheses regarding possible aetiology and treatment discussed.

Aged↗
PubMed1992

Examination of parameters influencing [3H]MK-801 binding in postmortem human cortex.

[3H]MK-801 binding was used as an index of the glutamate receptor N-methyl-D-aspartate-subtype channel to examine the influence of gender, age, mode of death (agonal status), interval between death and autopsy (postmortem delay), and time in storage at -70 degrees C in well washed homogenate preparations from postmortem human frontal cortex. Basal binding and the modulatory effects of glutamate, glycine, spermidine, and zinc were examined with respect to these variables. Basal binding was sensitive to agonal status, being higher in sudden death cases. The effect of added glutamate and glycine was sensitive to age, with a trend toward lower binding with increasing age. The effect of added spermidine alone was sensitive to storage time at -70 degrees C, the binding being higher with longer storage time. The effect of added zinc was also sensitive to postmortem delay, with zinc causing a greater reduction in binding with shorter postmortem delays. Thus, with the exception of gender, all variables examined influenced [3H]MK-801 binding, highlighting the attention that should be given to these factors in postmortem studies in normal and diseased human subjects.

Aged↗
PubMed1992

Nerve growth factor receptor-like immunoreactivity in the human spinal cord.

Nerve growth factor (NGF) receptor-like immunoreactivity has been demonstrated in the normal human adult spinal cord using the monoclonal antibody ME20.4. Intense immunoreactivity was associated with fibres and terminals in the substantia gelatinosa. In lamina IX the neuropil demonstrated punctate staining, the motor neurons themselves being negative. At thoracic levels occasional neurons of the intermediolateral column cell group were NGF receptor positive. Fine axonal and punctate terminal reactivity was observed in the gracile fasciculus, corresponding to axons in transverse section. Similar, though slightly less dense immunoreactivity was observed in the cuneate fasciculus. The demonstration of NGF receptor immunoreactivity may provide a useful marker of sensory innervation in the human spinal cord.

Adolescent↗
PubMed1991

Neocortical concentrations of neuropeptides in senile dementia of the Alzheimer and Lewy body type: comparison with Parkinson's disease and severity correlations.

Corticotropin releasing hormone (CRH), somatostatin (SRIF), and arginine vasopressin (AVP) concentrations were estimated using radioimmunoassay in the temporal and occipital cortices in postmortem brain from patients clinically and neuropathologically diagnosed as senile dementia of the Lewy body type (SDLT), senile dementia of the Alzheimer type (SDAT), and Parkinson's disease (PD) and from neurologically normal controls. The concentration of temporal and occipital neocortical CRH was diminished in both SDAT and SDLT compared to control values, whereas SRIF was reduced only in temporal cortex in both these conditions. In contrast, the concentrations of both CRH and SRIF were unaltered in PD. The concentrations of AVP in SDLT, SDAT, and PD were similar to those found in the control groups. The decrement in SRIF, but not CRH, was found to be correlated with some indices of severity of illness in SDAT; a similar but nonsignificant trend for SRIF was observed in SDLT.

Aged↗
PubMed1991

The quantitative autoradiographic distribution of [3H]MK-801 binding sites in the normal human spinal cord.

The distribution of NMDA receptors in the normal human spinal cord has been investigated using the non-competitive channel blocking agent MK-801. Specific [3H]MK-801 binding was present throughout the spinal grey matter at all segmental levels, the greatest density of binding being found in the substantia gelatinosa. Focal areas of high binding were also found in a distribution corresponding to lower motor neurones in the ventral horns. This study provides anatomical evidence that NMDA receptors are likely to be important in motor as well as sensory spinal synaptic transmission. The anatomical distribution of NMDA receptors in relation to motor neurone somata may have important implications in selective vulnerability to excitotoxic injury.

Aged↗
PubMed1991

Comparison of Ca(2+)-activated proteinase enzyme and endogenous inhibitor activity 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 determined the levels of Ca(2+)-activated proteinase (principally calpain II) and endogenous inhibitor (calpastatin) activity in normal and Alzheimer's disease cases, following fractionation of parietal cortex (grey and white matter) via anion-exchange chromatography. The chromatographic elution profiles and levels of calpain II activity were found to be similar in grey and white matter in both normal and Alzheimer's disease cases. The characteristics of calpain II, including Ca2+ concentration required for optimum activity for enzymes partially purified from normal or Alzheimer's disease cortex were identical. Similarly, the chromatographic elution profiles and levels of total calpastatin activity (approximately equal to that for calpain II activity) were found to be similar in grey and white matter from normal and Alzheimer's disease cases. These data suggest that the characteristic neurodegeneration associated with Alzheimer's disease does not result from alteration in the level of activity or characteristics of the calpain/calpastatin system in the cerebral cortex of patients with this disorder.

Aged↗
PubMed1991

Cortical serotonin-S2 receptor binding in Lewy body dementia, Alzheimer's and Parkinson's diseases.

The binding of the selective 5-HT2 antagonist [3H]ketanserin has been investigated in the temporal cortex of patients with Alzheimer's disease (SDAT), Parkinson's disease (PD), senile dementia of Lewy body type (SDLT) and neuropathologically normal subjects (control). 5-HT2 binding was reduced in SDAT, PD with dementia and SDLT. SDAT showed a 5-HT2 receptor deficit across most of the cortical layers. A significant decrease in 5-HT2 binding in the deep cortical layers was found in those SDLT cases without hallucinations. SDLT cases with hallucinations only showed a deficit in one upper layer. There was a significant difference in cortical layers III and V between SDLT without hallucinations and SDLT with hallucinations. The results confirm an abnormality of serotonin binding in various forms of dementia and suggest that preservation of 5-HT2 receptor in the temporal cortex may differentiate hallucinating from non-hallucinating cases of SDLT.

Aged↗
PubMed1991

Dementia: the neurochemical basis of putative transmitter orientated therapy.

The neurotransmitter deficits of dementias, including Alzheimer's dementia, Lewy body dementia and Parkinson's disease are discussed in relation to cognitive and behavioural impairments together with neuropathological changes and available data on the status of receptor transmembrane signalling. Potential therapeutic strategies for dementia are outlined based on the following systems: excitatory amino acids, gamma-amino butyric acid, acetylcholine (muscarinic and nicotinic), noradrenaline, serotonin and peptides. These include the attenuation of transmitter deficits by agonists and agents inhibiting transmitter breakdown and support for surviving neurons by suppression of inhibitory inputs, trophic factors and neural implantation.

Animals↗
PubMed1991

Topography, extent, and clinical relevance of neurochemical deficits in dementia of Lewy body type, Parkinson's disease, and Alzheimer's disease.

Cholinergic and monoaminergic (dopaminergic and serotonergic) activities have been examined in postmortem brain tissue in senile dementia of Lewy body type, Parkinson's disease, and Alzheimer's disease. Quantitative data suggest that although extrapyramidal symptoms relate to striatal levels of dopamine, cognitive impairment is most closely associated with cholinergic (but not monoaminergic) deficits in temporal and archicortical areas. Hallucinations, which are most frequent in Lewy body dementia, appear to be related to an extensive cholinergic deficit in temporal neocortex and the resulting imbalance between decreased cholinergic and relatively preserved serotonergic activities. Topographic analyses such as these including consideration of quantitative "threshold" effects, may be relevant to the future anatomic focus of neurochemical investigations in dementia and to the development of appropriate experimental models.

Adult↗
PubMed1991

Neurotransmitters and diseases of the brain.

The success of drugs targeted to specific transmitter systems in treating various psychiatric and neurological disorders is currently based on both empirical and rational approaches. Hopes for new rationally based therapies, especially those which may slow the progress of neurodegenerative disorders, continue to spring from an ever-expanding literature on transmitters and CNS disease, which is reviewed in this article.

Brain Diseases↗
PubMed1991

Nerve cell loss in the thalamus in Alzheimer's disease and Parkinson's disease.

Serial sections through the thalamus from the fixed right cerebral hemispheres of 15 cases (5 Parkinson's disease, 5 Alzheimer's disease (AD) and 5 controls) were used to obtain quantitative estimates of neuronal loss, neurofibrillary tangle formation and Lewy body inclusions within individual thalamic nuclei. Severe neuronal loss and tangle formation were evident in the anterodorsal nucleus from the AD cases. Nerve cell damage was also present in the centromedian nucleus but was not associated with tangle formation and occurred in all but 2 of the brains examined. It is likely that the anterodorsal neurons are damaged locally by the Alzheimer's disease process whereas the changes in the centromedian nucleus may be related to ageing.

Aged↗
PubMed1990

Fimbria-fornix lesions in aged rats cause increased carbachol-stimulated phosphoinositide hydrolysis in the hippocampus, but no change in muscarinic receptor binding.

Electrolytic lesions of the fimbria/fornix in 26-month-old rats led to an enhanced phosphoinositide (PI) hydrolysis in response to carbachol in hippocampal slices, 11-15 days after surgery. The lesions caused a 78% reduction of choline acetyltransferase but no change in muscarinic binding. The PI response to carbachol and the enhancement of this after lesioning were not as great as that previously reported in young adult rats.

Aging↗
PubMed1990

Cortical concentrations of corticotropin-releasing hormone and its receptor in Alzheimer type dementia and major depression.

Corticotropin-releasing hormone-immunoreactivity (CRH-IR) and CRH receptors (binding capacity and affinity) were measured in postmortem cortical areas from depressed subjects, two groups of senile dementia of the Alzheimer type (SDAT), and age-, sex-, and postmortem-delay-matched controls. No difference in CRH-IR and CRH receptor status between depressed subjects and controls was noted. CRH-IR was decreased in all cortical areas in SDAT, with a corresponding increase in CRH receptor binding capacity (with no change in affinity) in occipital cortex. No effects of postmortem delay were seen. It is suggested that the increase in CRH receptor numbers in SDAT is related to the degree of distribution of pathological involvement in specific regions.

Aged↗