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R H Perry

Publications and source records attributed to R H Perry.

At least 55 records · Page 3Linked to original sources
PubMed1994

A detailed anatomical analysis of neurotransmitter receptors in the putamen and caudate in Parkinson's disease and Alzheimer's disease.

Autoradiography allows precise anatomical matching as well as quantification of receptor density and is an ideal procedure to investigate neurotransmitter receptor distribution. Post mortem tissue from the caudate and putamen was investigated in cases of Parkinson's disease, Alzheimer's disease and age matched controls. Autoradiography was used to determine benzodiazepine, muscarinic cholinergic, D1 and D2 dopamine receptor density in these regions. This work shows that within the control group there is significantly higher benzodiazepine receptor density in the medial portion of the caudate and putamen when compared to lateral region. In the caudate nucleus there is a 15% (not significant) decrease of these receptors from rostral to caudal, no such decrease was present in the putamen. Muscarinic and both D1 and D2 dopamine receptors were evenly distributed in the control cases. Significant abnormalities in Parkinson's disease included loss of benzodiazepine receptors in the mid and caudal portions of the putamen and a decrease in muscarinic receptor density in the rostral putamen in Parkinson's disease.

Alzheimer Disease↗
PubMed1994

The effect of age on cerebral oedema, cerebral infarction and neuroprotective potential in experimental occlusive stroke.

A model of occlusive stroke in the aging brain has been developed and used to evaluate the effects of age upon cerebral infarction, cerebral oedema and neuroprotective potential. Focal ischaemia following left middle cerebral artery occlusion has been compared in aged (30 month) and adult (< 17 month) rats, with histological assessment of infarct volume and analysis of specific gravity as an index of cerebral oedema. Aging was associated with a significant increase in cerebral infarct size. The mean infarct volume in aged rats was 40.5% +/- 2.6% of the hemisphere volume, compared to 30.9% +/- 0.7% in adults (p < 0.01). Pre-treatment with the competitive N-Methyl-D-Aspartate (NMDA) receptor antagonist 3-(2-Carboxy Piperazin-4-yl)Propyl-l-Phosphonate (D-CPP-ene) reduced infarct volumes in both age groups to 33.0% +/- 1.8% and 20.7% +/- 3.2% in aged and adult animals, respectively (p < 0.05). There was significantly less oedema of the cerebral cortex in D-CPP-ene pre-treated rats; mean cortical specific gravity 4 hours post-infarction was 1.0381 +/- 0.0013 in untreated aged rats and 1.0391 +/- 0.0014 in untreated adults, compared to 1.0458 +/- 0.0031 in treated aged rats and 1.0442 +/- 0.0014 in treated adults (p < 0.05). At 24 hours post-infarction, D-CPP-ene pre-treated aged rats had a mean cortical specific gravity of 1.0403 +/- 0.0006 compared to 1.0361 +/- 0.0014 in untreated aged animals (p < 0.05). This study has demonstrated an age-related increase in cerebral infarct size, but has shown that the aging brain is amenable to neuroprotection by NMDA receptor antagonism.

Age Factors↗
PubMed1994

The clinical diagnosis and misdiagnosis of senile dementia of Lewy body type (SDLT).

BACKGROUND: Current clinical classifications do not contain specific diagnostic categories for patients with senile dementia of the Lewy body type (SDLT), recently proposed as the second commonest neuropathological cause of dementia in the elderly. This study determines how existing clinical diagnosis systems label SDLT patients and suggests how such patients may be identified. METHOD: A range of clinical diagnostic criteria for dementia were applied to case notes of autopsy-confirmed SDLT (n = 20), dementia of Alzheimer type (DAT; n = 21) and multi-infarct dementia (MID; n = 9) patients who had received psychogeriatric assessment. The predictive validity of each set of clinical criteria was calculated against the external criterion of neuropathological diagnosis. RESULTS: Many SDLT patients erroneously met criteria for MID (35% with Hachinski scores > or = 7) or for DAT (15% by NINCDS 'probable AD', 35% by DSM-III-R DAT and 50% by NINCDS 'possible AD'). Up to 85% of SDLT cases could be correctly identified using recently published specific criteria. CONCLUSIONS: SDLT usually has a discernible clinical syndrome and existing clinical classifications may need revision to diagnose correctly such patients.

Aged↗
PubMed1994

An evaluation of the predictive validity and inter-rater reliability of clinical diagnostic criteria for senile dementia of Lewy body type.

Several recent autopsy studies suggest that senile dementia of Lewy body type (SDLT) may be the second most common neuropathologic cause of dementia in the elderly, accounting for 7 to 30% of all cases. Operational criteria for the antemortem clinical diagnosis of SDLT have already been proposed by our group. The performance of these is now examined by randomizing the case notes from a new series of SDLT, Alzheimer, and multi-infarct dementia patients for psychiatric assessment by four raters of varying clinical experience and blind to pathologic diagnosis. Using the SDLT criteria, the two most experienced raters agreed in 94% of cases (kappa = 0.87), with the least experienced rater agreeing in 78% (kappa = 0.50). Diagnostic specificity for SDLT was uniformly high (90.0 to 97.0%), with a mean sensitivity of detection of 74%, and was greater by the experienced (90.0%) than the least experienced (55%) clinician. The antemortem identification of SDLT patients can therefore be achieved with a high degree of diagnostic specificity using such operationalized criteria, although there remains a minority of patients who present with either "typical" Alzheimer-type symptoms or with paranoid or delusional symptoms in the absence of substantial cognitive impairment. Sensitivity to neuroleptics may be a useful diagnostic pointer in these patients.

Aged↗
PubMed1994

Influence of apolipoprotein E genotype on senile dementia of the Alzheimer and Lewy body types. Significance for etiological theories of Alzheimer's disease.

Alzheimer's disease (AD) is associated with an increased frequency of the apolipoprotein E type epsilon 4 allele. To address both the disease and the allele specificity of this association, we have examined the apolipoprotein E allele distribution in 255 elderly persons including those with autopsy-confirmed AD, senile dementia of the Lewy body type (SDLT), vascular dementia, Parkinson's disease (PD) or Huntington's disease and in nondemented controls either with or without coronary complications. The epsilon 4 allele frequency was increased in SDLT (0.365) and AD (0.328) as compared with controls (0.147), PD (0.098), or Huntington's chorea (0.171). Coronary disease and vascular dementia were associated with marginally higher epsilon 4 allele frequencies than in controls. In PD, amyloid beta-protein accumulated to a greater extent in those cases possessing an epsilon 4 allele than in those without. Those PD cases with dementia were not distinguished from either controls or PD cases without dementia, whether tested biochemically or by apolipoprotein E genotype. It is the comparison of the results in AD and SDLT that yielded the most significant findings. There was a 1.8-fold excess of amyloid beta-protein in AD as compared with controls, and the levels in SDLT were intermediate between those in AD and controls. In contrast, AD was discriminated from both controls and SDLT by the substantial accumulation of paired helical filament tau and phosphorylated tau (both increased more than 20-fold as compared with controls). SDLT was nevertheless characterized by an increased epsilon 4 allele frequency in the absence of significant tau pathology (at least 10-fold less than that in AD). These findings indicate that tau processing is more specifically associated with AD than is amyloid beta-protein accumulation and that presence of the epsilon 4 allele is not an etiological factor that accounts for tau pathology.

Aged↗
PubMed1993

Transmitters in the developing and senescent human brain.

During development and throughout adult life, modeling of CNS structure and function occurs as a result of experience. Transmitters play a central role in this mechanism both directly and indirectly (through control of neurotrophin expression) by governing synapse formation, elimination or consolidation. Cholinergic and excitatory amino acid transmitter system activities have been examined in postmortem human brain obtained from normal individuals varying from the prenatal period to old age. Whereas glutamate NMDA receptor binding (measured using MK801) was not substantially altered across the postnatal period, dramatic and differing patterns of choline acetyltransferase (ChAT) activity were evident. Thus, in the cerebellum, ChAT activity was 10-fold higher in fetal compared to adult individuals whereas in the hippocampus there was little or no activity in the fetus and activity rose postnatally to reach a maximum in middle age and then declined to half that level by the tenth decade. Acetylcholinesterase (AChE) histochemical reactivity paralleled the developmental pattern for ChAT in the hippocampus and adjacent cortex with respect to fiber reactivity. These findings indicate that cholinergic synaptic plasticity may be restricted to the prenatal period in cerebellum but occur in both the postnatal period and throughout adult life in the hippocampus and cortex, a concept consistent with the temporal and regional expression of cholinoneurotrophins (NGF and related peptides). Vulnerability of the hippocampus and cortex to age-related pathology such as beta-amyloidosis and neuritic plaque formation may relate to the extended period of cholinergic synaptic sculpting in these areas.

Adult↗
PubMed1993

Regional patterns of cholinergic and glutamate activity in the developing and aging human brain.

The levels of choline acetyltransferase (ChAT) and the binding activity of N-methyl-D-aspartate (NMDA) and non-NMDA receptors have been measured in the hippocampus, entorhinal cortex, frontal cortex and cerebellum, in a series of human brains from 24 weeks gestation to 100 years. The patterns of ChAT and glutamate receptor activity during aging and development were strikingly different in the different brain areas. In the hippocampus and associated cortex, ChAT activity did not reach a peak until middle age, when it almost immediately started to decline by 50-60% to the 10th decade, whereas in the frontal cortex ChAT peaked transiently in the infant and then stayed constant during aging. In the cerebellum ChAT activity was very high in the foetus and fell in the neonate to maintain a constant level more in line with the concentrations found in the other brain areas through the rest of life. The high levels of ChAT in the foetal cerebellum were not associated with high acetylcholinesterase (AChE) content, which tended to increase during development, and was present initially in Purkinje cells (foetus and neonate) and the molecular layer in the adult. In the hippocampus and entorhinal cortex, autoradiographic [3H]MK-801 binding was relatively constant throughout life, however, [3H]CNQX binding rose from the perinatal period up to a peak in the 1st or 2nd decade and then tended to fall with age. In the cerebellum, autoradiographic binding of both ligands rose from the foetal period to reach a plateau by the age of 10 years and there was no apparent further change during aging. These data on cholinergic and glutamatergic phenotypic changes during development and senescence reflect marked variations in regional plasticity and aging within and between the two transmitter systems and are likely to contribute to our understanding of their role in the different brain areas investigated.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1993

Autoradiographic comparison of the distribution of [3H]MK801 and [3H]CNQX in the human cerebellum during development and aging.

The autoradiographic distribution of N-methyl-D-aspartate (NMDA) and D,L-a-amino-3-hydroxyl-5-methyl-4-isoxazoleproprionic acid/quisqualate (AMPA/QUIS) receptors was determined in cerebellum obtained at autopsy from 37 human individuals, aged from 24 weeks gestation to 95 years. [3H]MK801 was used to label the NMDA receptor and [3H]CNQX to label the AMPA/QUIS receptor. AMPA/QUIS receptors were concentrated in the cerebellar molecular layer, and NMDA receptors in the granular layer. Significant (3- to 4-fold) increases in binding were seen for both ligands from the fetal to neonatal periods in the molecular layer (CNQX) and in both molecular and granular layers (MK801). MK801 binding in the molecular layer continued to increase with age up to the tenth decade and together with binding in the granular layer, increased 2-fold between 10-40 years. The Purkinje cell layer was negative for MK801 binding until the 6-7th decade when it became positive. [3H]CNQX binding in the molecular layer increased significantly with age between the fetal period and the tenth decade, whereas in the granular layer binding increased from neonate to 40 years, but then decreased significantly from 60 years to the tenth decade. Lamination of the molecular and granular layers was absent during the fetal period and appeared with both ligands during the neonatal period. These marked differences in age-related expression of ligand binding sites in the granular layer during development and aging are of potential significance in relation both to selective vulnerability to ischemia, and synaptic plasticity and remodelling related to neuronal loss in senescence.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1993

Cytogenetic abnormalities in a disseminated medulloblastoma.

A 3-year-old girl developed central nervous system, bone and bone marrow metastases, and hypercalcaemia shortly after presentation with medulloblastoma. Cytogenetic studies of the involved bone marrow showed multiple abnormalities including iso(17q). This chromosome rearrangement has been reported in other cases of recurrent or disseminated medulloblastoma. More studies are required relating the karyotypes of medulloblastomas to long-term outcome to determine if the presence of iso(17q) is a prognostic factor in this malignancy.

Bone Neoplasms↗
PubMed1993

Monoaminergic activities in Lewy body dementia: relation to hallucinosis and extrapyramidal features.

Serotonergic (5-HT) and dopaminergic activities have been examined in Lewy Body Dementia (LBD) and compared with Parkinson's disease (PD) and Alzheimer's disease (AD). In the neocortex the LBD subgroup experiencing hallucinations was distinguished from the other categories by an increase in the 5HIAA:5HT ratio measured in frontal cortex and by the serotonergic (5-HIAA or 5-HIAA:5-HT): cholinergic (choline acetyltransferase) ratio in frontal and temporal cortex. In the neostriatum (caudate nucleus), loss of dopamine and increased HVA:dopamine ratio correlated with the reduction in substantia nigra neurons in LBD but not PD, despite the greater loss of neurones and dopamine and the higher dopamine turnover ratio in PD. LBD patients experiencing severe Parkinsonism as a result of neuroleptic treatment tended to have lower neuron counts, in combination with higher turnover ratios, than the remainder. Qualitative differences between LBD and PD included decreased cortical 5-HT turnover in PD compared with the increase in LBD. There were no significant changes in any parameter in AD, with the exception of a reduction in temporal cortex 5HIAA. The results suggest that although the neurochemical pathology of LBD and PD involves similar systems, the nature of the derangements differs sufficiently between the diseases to account for differences in symptomatology.

Aged↗
PubMed1993

Detection of Lewy bodies in Trisomy 21 (Down's syndrome).

The presence of cortical senile plaques and neurofibrillary tangles sufficient to warrant a neuropathological diagnosis of Alzheimer's disease is well established in middle-aged individuals with Trisomy 21 (Down's syndrome). In contrast a relationship between Down's syndrome and Lewy bodies, one of the major neuropathological features of Parkinson's disease, has not been previously reported. In a clinico-neuropathological survey of 23 cases of Down's Syndrome, two patients, aged 50 and 56 years respectively, were found to have Lewy body formation in the substantia nigra in addition to cortical Alzheimer-type pathology. Neither case showed significant substantia nigra neuron loss although locus coeruleus loss was present in both. Since substantia nigra Lewy bodies are a characteristic neurohistological feature of idiopathic Parkinson's disease, their occurrence in cases of Down's syndrome with evidence of Alzheimer-type pathology supports an aetiopathological connection between Parkinson's disease, Alzheimer's disease, and Down's syndrome; and suggests that common pathogenic mechanisms may underlie aspects of neuronal degeneration in these three disorders, some of which may relate to aberrant chromosome 21 expression.

Adult↗
PubMed1993

p53 protein overexpression identifies a group of central primitive neuroectodermal tumours with poor prognosis.

Primitive neuroectodermal tumours (PNET's) or medulloblastomas are common primary brain tumours of childhood. Current treatment protocols achieve 50-60% cures. However, it has proved difficult to develop better treatment for the remaining patients because prognostic factors are not established. We have investigated the prognostic value of p53 protein expression in 87 PNET's using immunohistochemistry with DO-7 and CM-1 antibodies on biopsy paraffin sections. Eight patients (9%) had intensely reactive tumour cell nuclei, and a significantly reduced survival (P = 0.002); only one survives and this with a recurrent tumour 50 months following diagnosis. Sixty eight per cent of patients had faintly reactive tumour cell nuclei, a reduced survival up to 4 years but a long term survival not significantly different (P = 0.41) from 23% of patients with p53 negative PNET's; the 10 year survival rates were 37% and 40%, respectively. Males had a reduced survival (P = 0.04) with a 2-fold relative risk of death compared to females. Multivariate analysis showed that intense overexpression of p53 protein identifies a group of PNET patients with a 7-fold relative risk of death compared to all other cases, irrespective of sex. This marked difference suggests the involvement of p53 in the pathogenesis of PNET's which have a particularly poor response to treatment, and should help to develop new therapies for this group of patients.

Adolescent↗
PubMed1993

Hippocampal p75 nerve growth factor receptor immunoreactivity in development, normal aging and senescence.

Using the monoclonal antibody ME 20.4, p75 nerve growth factor (NGF) receptor immunoreactivity has been studied in the hippocampus and adjacent cortex in a series of 57 cases ranging in age from 24 weeks gestation to 95 years of age. The activity of the neurotransmitter-synthesizing enzyme choline acetyltransferase (ChAT), the activity of which is regulated by NGF, has also been determined in parallel experiments. p75 NGF receptor immunoreactivity was detected in the fetal neocortex as nerve terminal staining, potentially derived from basal forebrain neurons which were positive for NGF receptor, and was also localized in nerve cells of the cerebral cortex. Cortical reactivity for NGF receptor increased with age up to the 4th decade thereafter remaining constant. NGF receptor reactivity localized to neocortical neuronal cell bodies was not present in the postnatal or adult brain. Hippocampal reactivity for the NGF receptor was not present before birth appearing first in the postnatal period and thereafter showing an identical development pattern to the neocortex. ChAT activity in the entorhinal cortex and hippocampus partially paralleled NGF receptor development being present in the neocortex in the fetus but not in the fetal hippocampal formation and increasing postnatally to reach maximum levels in the 4th decade. Whilst entorhinal cortex ChAT values remain relatively constant with ageing, hippocampal ChAT declined with age after the 4th decade. The results may have implications for the aetiology of age-related cholinergic deficits in the hippocampus.

Adolescent↗
PubMed1992

Iron and aluminium in relation to brain ferritin in normal individuals and Alzheimer's-disease and chronic renal-dialysis patients.

Ferritin has been isolated and its subunit composition, iron and aluminium content determined in the cerebral cortex and cerebellum of normal individuals and in the cerebral cortex of Alzheimer's-disease and renal-dialysis patients. An e.l.i.s.a. for ferritin has been developed and the ferritin, non-haem iron and aluminium content of the parietal cortex were determined in normal individuals and Alzheimer's-disease patients. It was found that ferritin from the cerebral cortex and cerebellum of normal individuals had a high H-subunit content, similar to that of heart ferritin. The subunit composition of ferritin isolated from the cerebral cortex was not significantly altered in Alzheimer's-disease or renal-dialysis patients. Ferritin from the cerebral cortex of normal individuals had only approx. 1500 atoms of iron per molecule and the iron content of ferritin was not significantly changed in Alzheimer's-disease or renal-dialysis patients. Ferritin isolated from the cerebral cortex of normal, Alzheimer's-disease and renal-dialysis patients had less than 9 atoms of aluminium per molecule. The failure to find increased concentrations of aluminium associated with ferritin in dialysis patients, who had markedly increased concentrations of aluminium in the cerebral cortex, shows that aluminium does not accumulate in ferritin in vivo. This has important implications for the toxicity of aluminium, since it implies that cells are unable to detoxify aluminium by the same mechanism as that available for iron. Comparison of the concentrations of ferritin, aluminium and iron in the parietal cortex from normal and Alzheimer's-disease patients showed that, whereas the concentration of aluminium was not increased, both ferritin and iron were significantly increased in Alzheimer's disease.

Aged↗
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↗