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P G Ince

Publications and source records attributed to P G Ince.

At least 91 records · Page 5Linked to original sources
PubMed1995

Distribution of AMPA-selective glutamate receptor subunits in the human hippocampus and cerebellum.

The distribution of AMPA-selective subunits, GluR1-4, was determined in the human hippocampus and cerebellum by in situ hybridization and immunocytochemistry. In the hippocampus, in situ hybridization revealed that GluR1 and GluR2 mRNAs were similarly distributed and highly expressed in the dentate gyrus, with lower levels in the CA regions. GluR3 and GluR4 mRNAs were expressed at very low levels. Immunocytochemical studies showed that GluR1- and GluR2/3-immunoreactivity were highest in the dentate molecular and granular layers. In the CA regions, GluR1 and GluR2/3 staining was observed in pyramidal cell bodies and surrounding neuropil and was more intense in CA4/3/2 compared with CA1. GluR4-immunoreactivity was low throughout the hippocampus. In the cerebellum, GluR1 and GluR4 transcripts were expressed in the granular and Purkinje cell/Bergmann glia layers. GluR2 mRNA was highly expressed in the granular layer and individual Purkinje cells, while GluR3 mRNA was not detectable in the cerebellum. GluR1- and GluR4-immunoreactivity were localized to Purkinje cells and putative Bergmann glia, as well as their processes extending into the molecular layer. GluR2/3 staining was intense in Purkinje cells, with moderate staining in the granular layer. Thus, GluR1-4 subunits are differentially distributed in the hippocampus and cerebellum. In addition, the distribution of subunit mRNA and protein correlate well with each other and with the glutamatergic neuroanatomy of the hippocampus and cerebellum.

Aged↗
PubMed1995

Unusual CT appearances with a supratentorial meningioma.

The majority of intracranial meningiomas are isodense, well-marginated masses, adjacent to a dural surface. They show intense uniform enhancement following intravenous contrast. Atypical appearances can occur. Hypodense meningiomas have been described due to necrosis, cystic change or lipidisation of the tumour. A meningioma is described which showed two unusual features on computed tomography-a uniformly hypodense mass on an unenhanced scan and only minimal contrast enhancement. Extensive lipidisation of the tumour was demonstrated histologically.

Brain↗
PubMed1995

Quantitative study of synaptophysin immunoreactivity of cerebral cortex and spinal cord in motor neuron disease.

Synaptophysin immunoreactivity can be quantified by image analysis to evaluate loss of presynaptic terminals in human neurodegenerative diseases. The extent and regional distribution of such loss is reported in motor neuron disease (MND). Autopsy samples of spinal cord and cerebral cortex were examined from 28 cases of MND and 28 age and sex matched controls. The MND group included individuals with amyotrophic lateral sclerosis (17[ALS]), and progressive muscular atrophy (11[PMA]). In the spinal cord, there was significant reduction of presynaptic terminals in the lateral ventral horn (15%) in both the ALS (p < 0.01) and PMA (p < 0.05) groups. Perisomatic synaptophysin profiles on lower motor neurons are preserved late in the disease and are not related to corticospinal innervation. Less marked presynaptic loss was demonstrable more widely in the medial ventral, intermediate and dorsal spinal grey matter (10%) in both ALS (p = 0.03) and PMA (p = 0.05). In the cerebral cortex no synaptic loss was demonstrated in motor or anterior cingulate regions in any of the MND cases. Spinal degeneration in MND is associated with loss of presynaptic terminals in all grey matter regions. It is most marked in the limb motor neuron area and is independent of corticospinal tract degeneration. The cerebral pathology of ALS is not associated with significant loss of presynaptic terminals in the cortical areas studied.

Adult↗
PubMed1995

G-protein mutations in human pituitary adrenocorticotrophic hormone-secreting adenomas.

Activating mutations of Gs alpha (gsp) and Gi2 alpha (gip) have been described in various endocrine neoplastic conditions. The objective of this study was to assess the prevalence of gsp and gip mutations in human adrenocorticotrophin hormone-secreting pituitary adenomas. Adrenocorticotrophin hormone production and secretion by pituitary corticotroph cells is under stimulatory control by corticotrophin-releasing factor, acting via the production of cyclic AMP. Interference with this regulatory pathway as a result of G-protein dysfunction could lead to disordered corticotroph cell function and growth. We have studied 32 corticotroph adenomas for the presence of gsp and gip mutations using site-directed oligonucleotide hybridization of polymerase chain reaction-amplified DNA. G-protein gene mutations were identified in three (9%) tumours: gsp mutations were demonstrated in two tumours at codon 227, and a gip mutation was identified in one tumour at codon 179. We did not observe a correlation between tumour phenotype and the presence of G-protein gene mutations. We conclude that G-protein gene mutations are an uncommon abnormality in corticotroph adenomas.

Adenoma↗
PubMed1995

Abnormally phosphorylated tau protein in senile dementia of Lewy body type and Alzheimer disease: evidence that the disorders are distinct.

The relationship between Alzheimer disease (AD) and dementia with Lewy bodies (senile dementia Lewy body type, or SDLT) and dementia in Parkinson's disease is unclear. AD pathology is characterised by both amyloid deposition and abnormal phosphorylation of tau in paired helical filaments (PHF-tau). In AD, abnormally phosphorylated PHF-tau is present in neurofibrillary tangles, in neuritic processes of senile plaques, and also in neuropil threads dispersed throughout the cerebral cortex. Cortical homogenates from 12 cases each of AD and SDLT, 13 cases of Parkinson's disease, and 11 normal controls were examined by Western blot analysis with antibodies that detect PHF-tau. No PHF-tau was found in Parkinson's disease or control cortex. No PHF-tau was found in SDLT cases without histological evidence of tangles. PHF-tau was detectable in SDLT cases with a low density of tangles, and large amounts of PHF-tau were present in AD cases. This study demonstrates that abnormally phosphorylated PHF-tau is only present where tangles are found and not in SDLT cases without tangles or with only occasional tangles. It is concluded that Lewy body dementias are distinct at a molecular level from AD.

Aged↗
PubMed1994

Iron, selenium and glutathione peroxidase activity are elevated in sporadic motor neuron disease.

Oxygen free radical damage is strongly implicated in the pathogenesis of familial motor neuron disease (MND) associated with mutation of the Cu/Zn superoxide dismutase gene, and may be relevant in sporadic MND. Selenium (Se) and iron (Fe) have important roles in free radical metabolism. Using neutron activation analysis we have demonstrated significant elevation of Se and Fe in lumbar spinal cord in MND cases (38) compared to controls (22). Analysis of enzymes involved in free radical scavenging showed a significant and specific increase in the activity of the selenoprotein enzyme glutathione peroxidase in MND spinal cord.

Glutathione Peroxidase↗
PubMed1994

The distribution of excitatory amino acid receptors in the normal human midbrain and basal ganglia with implications for Parkinson's disease: a quantitative autoradiographic study using [3H]MK-801, [3H]glycine, [3H]CNQX and [3H]kainate.

Quantitative receptor autoradiography using [3H]MK-801, [3H]glycine, [3H]CNQX and [3H]kainate was employed to determine the distribution and density of excitatory amino acid (EAA) binding sites in the midbrain and basal ganglia of the normal human nervous system. Detailed knowledge of the anatomy and subtype specificity of glutamate receptors is important both in understanding the normal physiology of basal ganglia neurotransmission and the pathophysiological changes occurring in diseases affecting the basal ganglia such as Parkinson's disease (PD). In PD, glutamate receptor activation may contribute to cell death of dopaminergic neurones in the substantia nigra. In addition, perturbation of glutamate neurotransmission resulting from dopamine depletion in the basal ganglia is likely to contribute to the clinical manifestations of motor dysfunction. The distribution and density of ligand binding representing N-methyl-D-aspartate (NMDA), AMPA (2-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) and kainate receptors has a heterogeneous distribution in the human midbrain and basal ganglia. In the substantia nigra relatively high densities of [3H]MK-801 and strychnine-insensitive [3H]glycine binding sites representing NMDA receptors were present, whereas only moderate densities of [3H]CNQX and [3H]kainate binding sites were present, compared to other regions. In both the medial globus pallidus and subthalamic nucleus, binding sites representing NMDA, AMPA and kainate receptors were all present at low density. These findings suggest that the clinical usefulness of modifying glutamatergic neurotransmission in these basal ganglia nuclei may be limited by the relatively low density of EAA binding sites present.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1994

Non-NMDA receptors in motor neuron disease (MND): a quantitative autoradiographic study in spinal cord and motor cortex using [3H]CNQX and [3H]kainate.

The distribution and density of non-NMDA receptors in spinal cord and motor cortex was compared in 10 cases of motor neuron disease (MND) and 8 neurologically normal controls by quantitative autoradiography using [3H]CNQX and [3H]kainate. In the motor cortex of MND cases, an increased density of [3H]kainate binding sites was observed which was most marked in the deep layers. No significant differences were observed in [3H]CNQX binding in the motor cortex between MND and control cases. In the spinal cord significantly increased densities of both [3H]CNQX and [3]kainate binding sites were found in the substantia gelatinosa and the intermediate grey matter in the MND group. The changes in [3H]kainate binding were observed only in the amyotrophic lateral sclerosis (ALS) subgroup of MND, while the changes in [3H]CNQX binding in the spinal cord were more marked in ALS compared to progressive muscular atrophy (PMA) cases. These findings provide evidence in support of a disturbance of glutamatergic neurotransmission in MND and suggest that there may be an increased excitatory drive to motor neurons via non-NMDA receptors. It is unclear at present whether the changes observed represent a compensatory response to loss of motor neurons in MND or a pathophysiological phenomenon contributing to motor neuron degeneration. Modulation of non-NMDA receptor activity may represent a possible target for therapeutic intervention in this disease.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1994

[3H]D-aspartate binding sites in the normal human spinal cord and changes in motor neuron disease: a quantitative autoradiographic study.

The distribution and density of glutamate transporter sites was determined in human cervical and lumbar spinal cord, by quantitative autoradiography using [3H]D-aspartate. In the normal human spinal cord (n = 8) there was specific binding of [3H]D-aspartate throughout the spinal grey matter, with the highest levels observed in the substantia gelatinosa and central grey matter. In the ventral horns, particularly at the L5 level, focal hot spots of binding were observed in a distribution corresponding to that of lower motor neuron somata. Comparison of motor neuron disease (MND) cases (n = 12) with normal controls showed a reduction in the density of [3H]D-aspartate binding in the intermediate grey matter and the substantia gelatinosa of the lumbar cord. These changes were more marked in the amyotrophic lateral sclerosis (ALS) compared to the progressive muscular atrophy (PMA) subgroup, and may be due to loss of glutamatergic terminals of the corticospinal tract. The changes observed in the cervical cord were milder and did not reach statistical significance. No differences were found between [3H]D-aspartate binding in the spinal cords of the normal controls and a neurological disease control group (n = 6), suggesting that the changes observed in MND are disease specific. These findings provide further evidence in support of a disturbance of glutamatergic neurotransmission in MND.

Adult↗
PubMed1994

Gender differences in the phenotypic expression of Alzheimer's disease in Down's syndrome (trisomy 21).

Twenty-eight individuals with typical Down's syndrome (DS) phenotype (17 males and 11 females; age range: 10-74 years) were investigated for gender differences in the phenotypic expression of Alzheimer-type pathology (ATP). Quantitative neuropathology was performed in the 4 neocortical lobes of the right hemisphere, by counting senile plaques (SP), and neurofibrillary tangles (NFT). ATP was present in 25 middle-aged (> 40 years) individuals (16 males and 9 females). Females had significantly higher (p = 0.03) mean neocortical NFT densities (36.6 per mm2; s.e.m. +/- 6.6) than males (17.9 per mm2; s.e.m. +/- 4.7). None of the females had NFT densities below 10 per mm2, compared with 6 males in whom NFT were either absent or seen in very low densities (< 4 per mm2). Assessment of SP densities in the same cortical regions showed non-significant differences in females (42.4 per mm2; s.e.m. +/- 5.1) compared with males (33.6 per mm2; s.e.m. +/- 2.1). There was clinical evidence of dementia in all the female (8/8) individuals who were prospectively assessed, compared with only 54% (7/13) of males. The male individuals without clinical dementia had absent or low neocortical NFT densities regardless of high SP densities. Female DS cases (mean age: 48.8 years; s.e.m. +/- 1.9) had an earlier onset of dementia than males (mean age: 53.6 years; s.e.m. +/- 1.3; p = 0.05). Female middle-aged DS individuals have an earlier onset, and a more severe form of AD which correlates with higher neocortical NFT rather than SP density.

Adenosine Triphosphate↗
PubMed1994

A quantitative autoradiographic study of [3H]kainate binding sites in the normal human spinal cord, brainstem and motor cortex.

The quantitative autoradiographic distribution of the kainate subtype of non-NMDA receptor in the normal human motor cortex, brainstem and spinal cord has been investigated using [3H]kainate. In the motor cortex specific [3H]kainate binding was present in all cortical laminae with the highest density in laminae and II and the upper part of III and lower densities in the middle and deep laminae. In the premotor cortex a band of high density was found in laminae V and VI as well as in the superficial laminae. In the normal brainstem kainate receptors had a heterogeneous distribution. Brainstem motor nuclei which tend to be affected in motor neuron disease (MND) had very low densities of binding sites, whereas the oculomotor nucleus had a higher density. Specific [3H]kainate binding was found throughout the spinal grey matter, the greatest density being found in the substantia gelatinosa and much lower densities in the rest of the grey matter including the ventral horns. Excitotoxicity at non-NMDA receptors has been implicated in the pathogenesis of MND. This study shows that the motor neuron groups vulnerable in MND express a low density of [3H]kainate binding sites and suggests that the density of kainate receptors does not account for selective vulnerability in this disorder.

Adult↗
PubMed1994

N-methyl-D-aspartate (NMDA) receptors in the spinal cord and motor cortex in motor neuron disease: a quantitative autoradiographic study using [3H]MK-801.

The distribution and density of NMDA receptors in spinal cord and motor cortex was compared in motor neuron disease (MND; 10 cases) and controls (8 cases) using [3H]MK-801 autoradiography. In the spinal ventral horn of MND cases, [3H]MK-801 binding was reduced and there were fewer focal hot spots of binding. These changes are likely to reflect loss of motor neurons (MN) bearing NMDA receptors. [3H]MK-801 binding was increased in intermediate spinal grey matter and deeper layers of the motor cortex in MND cases compared to controls. This may represent either an adaptive response to MN loss or a pathophysiological phenomenon contributing to MN degeneration.

Aged↗
PubMed1994

Oncoprotein immunoreactivity in human pituitary tumours.

OBJECTIVE AND DESIGN: The immediate early gene locus AP-1, incorporating the cellular oncogenes c-fos and c-jun (and their oncoprotein products Fos and Jun respectively) play a key role in regulating cell growth and differentiation. The myc-gene is also known to promote cell growth. In order to investigate the possible role of these oncogenes in human pituitary adenomas, Fos, Jun and Myc oncoprotein immunoreactivities were assessed in surgically resected pituitary adenomas in relation to in-vivo characteristics (hormone secretion, size and invasiveness) and an in-vitro index of cell proliferation (Ki-67 immunoreactivity). Thirty-three human pituitary adenomas and 16 normal pituitary glands were examined. MEASUREMENTS: Oncoprotein immunoreactivity was recorded as present (+) or absent (-), and Ki-67 labelling indices were scored quantitatively. Tumour size was scored from CT scan appearances and radiographic evidence of bone erosion was noted. RESULTS: Oncoprotein immunoreactivity was present in a total of 32/33 cases. Myc immunoreactivity was restricted to the only ACTH-secreting tumour in the series (1/33). Ki-67 immunoreactivity was present in 24/32 cases and labelling indices varied from 0.1 to 3.2%. CONCLUSIONS: Oncoprotein immunoreactivity did not correlate with hormonal profile, bone erosion or the size of the proliferating compartment estimated by Ki-67 labelling indices. Although oncoprotein expression is common in human pituitary adenomas, its significance remains to be elucidated.

Adenoma↗
PubMed1993

Autoradiographic distribution of binding sites for the non-NMDA receptor antagonist [3H]CNQX in human motor cortex, brainstem and spinal cord.

The distribution of non-NMDA receptors in the normal human motor cortex, brainstem and spinal cord has been investigated using [3H]CNQX. In the motor and premotor cortex, specific [3H]CNQX binding was present in all cortical laminae with the highest density of binding sites in laminae I, II and the upper part of III. In the normal brainstem, non-NMDA receptors labelled by [3H]CNQX had a heterogeneous distribution. Brainstem motor nuclei subserving eye movements, which tend to be spared in motor neuron disease (MND), had a higher density of [3H]CNQX binding sites compared to other cranial nerve motor nuclei (VII, X, XII) which tend to be affected. Specific [3H]CNQX binding was present throughout the spinal grey matter, the greatest density of binding being found in the substantia gelatinosa. Excitotoxicity at non-NMDA receptors has been implicated in chronic neurodegenerative diseases such as motor neuron disease. This study suggests that the density of non-NMDA receptors, labelled by [3H]CNQX, does not account for selective vulnerability of motor neurons in this disorder.

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