Fulminant encephalopathy due to the catastrophic primary antiphospholipid syndrome.
Explore the source record for details and available documents.
Antiphospholipid Syndrome↗
Biomedical subjects
P G Ince
Publications and source records attributed to P G Ince.
Selective loss of neurofilament proteins after exposure of differentiated human IMR-32 neuroblastoma cells to oxidative stress.
Millimolar concentrations of ascorbate in the presence of iron can cause neuronal cell death. This study shows that the human neuronal cell line IMR-32 is sensitive to ascorbate and that cytotoxicity can be blocked by the antioxidant enzymes Cu/Zn-superoxide dismutase and catalase. There was a selective loss of neurofilament proteins after exposure to 5 or 10 mM ascorbate, as assessed by immunostaining and by Western blotting. Loss of actin or tubulin was not seen, suggesting that loss of neurofilaments is a sensitive and selective marker for free radical damage in these cells.
Ascorbic Acid↗
Apolipoprotein E genotype and Alzheimer's disease in an elderly Norwegian cohort.
Apolipoprotein E (Apo E) genotyping was performed on an autopsy cohort of neuropathologically verified non-demented controls and subjects with Alzheimer's disease (AD) resident in nursing homes in the Oslo area. AD was associated with a significantly increased frequency of the Apo E epsilon 4 allele; the frequency of the epsilon 2 and epsilon 3 alleles was lower in AD but not significantly so. Age at death in the control group and the AD group did not differ significantly; neither did age at death nor age at onset of dementia in AD vary according to Apo E genotype, though tendencies towards an earlier age at death was seen in individuals with epsilon 4/4 and earlier age at onset dementia in the presence of an epsilon 4 allele and a later age of onset the presence of an epsilon 3 allele were seen. Possession of an epsilon 2 allele had no effect on age at onset of dementia or age at death. Among the possible genotypes there was a trend towards a progression of earliest onset epsilon 4/4, epsilon 2/4, epsilon 3/4, epsilon 3/3, epsilon 2/3 latest onset of dementia and longest duration epsilon 2/4, epsilon 4/4, epsilon 3/4, epsilon 3/3, epsilon 2/3 to shortest duration of dementia.
Age of Onset↗
Molecular biology of APO E alleles in Alzheimer's and non-Alzheimer's dementias.
Current research into the aetiology of the dementias is focused upon genetic factors which give rise to the disease process. Recently the Apolipoprotein E gene (APO E) and in particular the epsilon 4 allele has been shown to be a risk factor for late onset Alzheimer's disease (AD) where there is an increased frequency of the epsilon 4 allele. The epsilon 4 allele has also been shown to reduce the age at onset of dementia in AD in a dose dependent manner, with the epsilon 2 allele having an opposing effect. We have genotyped a large series of clinically and neuropathologically confirmed cases of AD and found the expected increase in the Apolipoprotein epsilon 4 allele frequency when compared to a control population. Similarly, in Lewy Body Dementia (LBD) an increased epsilon 4 frequency is also found though a normal epsilon 2 frequency exists, unlike in AD where the epsilon 2 frequency is reduced. No changes in APO E allele frequencies were found in presenile AD, Parkinson's disease with or without dementia, or in Down's syndrome. No association was found between any of the APO E alleles and the histopathological indices of AD, cortical senile plaques and neurofibrillary tangles, in any disease category. Neurochemical indicators of AD, loss of choline acetyltransferase activity was also unaffected by APO E genotype. Whilst their appears to be a strong association between the APO E allele and AD and also in LBD, other related neurodegenerative disorders associated with dementia do not show such a linkage. Changes in the epsilon 2 allele frequency may indicate a genetic difference between AD and LBD. The epsilon 4 allele does not appear to influence the burden of AD type pathology and this is particularly relevant given the relative lack of NFT in LBD indicating that factors other than SP or NFT may govern the onset of dementia.
Alleles↗
A quantitative comparison of plaque types in Alzheimer's disease and senile dementia of the Lewy body type.
In a previous study we reported no difference in the overall beta-amyloid protein (beta AP) load between Alzheimer's disease (AD) and senile dementia of the Lewy body type (SDLT). However, it is possible that differences in the morphology of beta AP plaque types exist, analogous to the differences in cytoskeletal pathology found in these two disorders. We have carried out a quantitative image analysis of plaque subtypes in the temporal lobe of AD (n = 8), SDLT (n = 9) and control (n = 11) cases. Measurements of beta AP load and plaque density were consistently higher in AD and SDLT than in controls. When AD and SDLT cases were compared no differences were seen in either the density or relative proportions of classic and diffuse plaques. Based on these results we suggest that the variation in the clinical course of these diseases reflects differences in the cytoskeletal pathology, whereas the final stages of profound dementia common to both disorders is associated with the deposition of beta AP.
Aged↗
Familial amyotrophic lateral sclerosis with a mutation in exon 4 of the Cu/Zn superoxide dismutase gene: pathological and immunocytochemical changes.
Detailed molecular pathology studies and clinicopathological phenotyping of familial amyotrophic lateral sclerosis (FALS) with characterised mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) will yield important insights into the pathogenesis of motor neuron degeneration. An autopsy case is described with the mutation E100G (exon 4) of the SOD1 gene in which full neuropathological examination including immunocytochemistry of ubiquitin and neurofilament epitopes was performed. The case falls into the category of "amyotrophic lateral sclerosis (ALS) with posterior column involvement." Critical analysis of the findings indicates a truly multisystem disorder in which ascending sensory pathways and components of the efferent cerebellar pathways are at least as severely affected as the motor system. Abnormal neurofilament phosphorylation was not a prominent feature. Ubiquitinated neuronal inclusions were infrequent except in the hippocampal denate granule cells where they were indistinguishable from sporadic cases of ALS-dementia. The motor cortex was preserved despite severe distal axonal loss in the corticospinal tract. These findings suggest a primary failure of axonal maintainance affecting several neuronal groups with long projecting axons. The differences and similarities compared to previously reported case with I113T (exon 4) and A4T (exon 1) mutations are discussed. Findings related to inflammatory cell infiltration, ubiquitination and neurofilament phosphorylation are discussed with reference to the pathogenesis of sporadic ALS.
Adult↗
Cytoplasmic, lysosomal and matrix protease activities in spinal cord tissue from amyotrophic lateral sclerosis (ALS) and control patients.
The histological identification of ubiquitin-conjugated protein deposits in spinal motor neurones of patients with amyotrophic lateral sclerosis (ALS) has suggested that an underlying abnormality of intracellular protein metabolism may be responsible for the pathogenesis of the disease. In an attempt to identify such an abnormality at the biochemical level, we have undertaken a systematic investigation of a representative range of proteolytic enzyme types comprising the two major pathways (cytoplasmic and lysosomal) of intracellular protein degradation, in spinal cord tissue from ALS and control cases. No evidence of a generalised alteration in protein catabolizing proteolytic enzymes in spinal cord tissue from ALS cases was found. Only proline endopeptidase and pyroglutamyl aminopeptidase (both cytoplasmic proteases) showed significantly altered activity (increased by 76% and 119%, respectively) in ALS cases compared to normal controls. In addition to their generalised role in intracellular protein degradation, these two enzymes are involved in the processing of thyrotrophin-releasing hormone (TRH) in CNS tissues. The selective increase in activity of proline endopeptidase and pyroglutamyl aminopeptidase in ALS may represent an adaptation to maintain excitatory drive to surviving motor neurons by increased processing of TRH to its active metabolite.
Aged↗
Distribution of alpha 1A, alpha 1B and alpha 1E voltage-dependent calcium channel subunits in the human hippocampus and parahippocampal gyrus.
The distribution of voltage-dependent calcium channel subunits in the central nervous system may provide information about the function of these channels. The present study examined the distribution of three alpha-1 subunits, alpha 1A, alpha 1B and alpha 1E, in the normal human hippocampal formation and parahippocampal gyrus using the techniques of in situ hybridization and immunocytochemistry. All three subunit mRNAs appeared to be similarly localized, with high levels of expression in the dentate granule and CA pyramidal layer. At the protein level, alpha 1A, alpha 1B and alpha 1E subunits were differentially localized. In general, alpha 1A-immunoreactivity was most intense in cell bodies and dendritic processes, including dentate granule cells, CA3 pyramidal cells and entorhinal cortex pre-alpha and pri-alpha cells. The alpha 1B antibody exhibited relatively weak staining of cell bodies but stronger staining of neuropil, especially in certain regions of high synaptic density such as the polymorphic layer of the dentate gyrus and the stratum lucidum and radiatum of the CA regions. The alpha 1E staining pattern shared features in common with both alpha 1A and alpha 1B, with strong immunoreactivity in dentate granule, CA3 pyramidal and entorhinal cortex pri-alpha cells, as well as staining of the CA3 stratum lucidum. These findings suggest regions in which particular subunits may be involved in synaptic communication. For example, comparison of alpha 1B and alpha 1E staining in the CA3 stratum lucidum with calbindin-immuno-reactivity suggested that these two calcium channels subunits may be localized presynaptically in mossy fibre terminals and therefore may be involved in neurotransmitter release from these terminals.
Aged↗
An immunocytochemical study of the distribution of AMPA selective glutamate receptor subunits in the normal human motor system.
Glutamate is the major mediator of fast excitatory neurotransmission in the mammalian central nervous system. Disturbances of this neurotransmitter system have been implicated in chronic degenerative neurological disease. Recently, major advances in our knowledge and understanding of the molecular biology of the glutamatergic receptor system have been made. It is now known that functional glutamate receptors consist of various combinations of some 20 identified subunits. A growing body of circumstantial evidence suggests that the non-N-methyl-D-aspartate subtype of glutamate receptors may mediate, at least in part, the selective motor neuron death seen in the human neurodegenerative disease amyotrophic lateral sclerosis. We have used subunit specific immunocytochemistry to study the distribution and potential subunit composition of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) selective glutamate receptors, (a subgroup of non-N-methyl-D-aspartate selective glutamate receptors formed by combinations of GluR1-4 subunits), in the human motor system. Motor neurons in the spinal cord, brainstem, and motor cortex were relatively strongly immunoreactive with the GluR2/3 subunit antibody, moderately so with the GluR4 subunit antibody, and showed relatively low levels of immunoreactivity with the GluR1 subunit antibody. This is the first detailed study of AMPA receptor subunit expression in the human motor system. Motor neurons express a distinct subunit profile when compared with other groups of neurons in the human nervous system. There were no significant differences in the pattern of relative AMPA subunit expression (GluR2/3 > or = GluR4 > GluR1) between groups of motor neurons typically affected (in the spinal cord and hypoglossal nucleus), or spared (oculomotor and Onufs nucleus) by the amyotrophic lateral sclerosis disease process. However, oculomotor motor neurons had higher levels of expression of all AMPA subunit proteins which may indicate greater AMPA mediated glutamatergic input in the normal function of this neuronal population. This study does not support a role for differential subunit composition of AMPA receptors in determining the selective vulnerability of motor neurons in amyotrophic lateral sclerosis. However, the overall density of receptors may be of importance.
Aged↗
Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop.
Recent neuropathologic autopsy studies found that 15 to 25% of elderly demented patients have Lewy bodies (LB) in their brainstem and cortex, and in hospital series this may constitute the most common pathologic subgroup after pure Alzheimer's disease (AD). The Consortium on Dementia with Lewy bodies met to establish consensus guidelines for the clinical diagnosis of dementia with Lewy bodies (DLB) and to establish a common framework for the assessment and characterization of pathologic lesions at autopsy. The importance of accurate antemortem diagnosis of DLB includes a characteristic and often rapidly progressive clinical syndrome, a need for particular caution with neuroleptic medication, and the possibility that DLB patients may be particularly responsive to cholinesterase inhibitors. We identified progressive disabling mental impairment progressing to dementia as the central feature of DLB. Attentional impairments and disproportionate problem solving and visuospatial difficulties are often early and prominent. Fluctuation in cognitive function, persistent well-formed visual hallucinations, and spontaneous motor features of parkinsonism are core features with diagnostic significance in discriminating DLB from AD and other dementias. Appropriate clinical methods for eliciting these key symptoms are described. Brainstem or cortical LB are the only features considered essential for a pathologic diagnosis of DLB, although Lewy-related neurites, Alzheimer pathology, and spongiform change may also be seen. We identified optimal staining methods for each of these and devised a protocol for the evaluation of cortical LB frequency based on a brain sampling procedure consistent with CERAD. This allows cases to be classified into brainstem predominant, limbic (transitional), and neocortical subtypes, using a simple scoring system based on the relative distribution of semiquantitative LB counts. Alzheimer pathology is also frequently present in DLB, usually as diffuse or neuritic plaques, neocortical neurofibrillary tangles being much less common. The precise nosological relationship between DLB and AD remains uncertain, as does that between DLB and patients with Parkinson's disease who subsequently develop neuropsychiatric features. Finally, we recommend procedures for the selective sampling and storage of frozen tissue for a variety of neurochemical assays, which together with developments in molecular genetics, should assist future refinements of diagnosis and classification.
Dementia↗
Oxidative damage and motor neurone disease difficulties in the measurement of protein carbonyls in human brain tissue.
It has been suggested in the literature that elevated oxidative protein damage, measured as protein carbonyls, is present in the nervous system of patients with sporadic motor neurone disease (MND). However, the actual reported levels of brain protein carbonyls vary over a wide range. We show here that this is probably due to the use of the different protocols for the carbonyl assay; results differ depending on when the dinitrophenylhydrazine reagent is added and at what stage in the procedure protein is assayed for the calculation of carbonyls on a unit protein basis. Using a range of different procedures, we were unable to confirm reports of elevated protein carbonyls in motor cortex from brains of patients with MND. We also measured thiobarbituric acid-reactive material in the brain samples using an HPLC-based TBA test in the presence of butylated hydroxytoluene. In general, there was no significant elevation of TBARS in MND motor cortex. However, four patients showed values higher than any of the control patients (both 'normal' control and 'disease control'). There was no correlation of TBARS with protein carbonyl values. We suggest that oxidative damage in motor cortex in sporadic MND, if it occurs, may be confined to a small group of patients and may affect different molecular targets in each patient.
Adult↗
The expression of neuronal voltage-dependent calcium channels in human cerebellum.
Little is known about the comparative distribution of voltage-dependent calcium channel subtypes in normal human brain. Previous studies in experimental animals have predominantly focused on the regional expression of single alpha 1 genes. We describe the preparation of riboprobes and antisera specific for human alpha 1A, alpha 1B and alpha 1E subunits and their application in comprehensive mapping studies of the human cerebellum. Within the cerebellar cortex, these pore forming proteins were found to have differential localisations when examined in adjacent sections. The alpha 1A and alpha 1B subunits broadly colocalised and were both present, though at apparently different levels, in the molecular, Purkinje and granule cell layers whilst alpha 1E was predominantly expressed in Purkinje cells. In the dentate nucleus, an area which has received little attention in previous studies, alpha 1A was highly expressed in regions in which Purkinje cell nerve terminals form synapses with deep cerebellar neurones.
Aged↗
Effect of apolipoprotein E genotype on Alzheimer's disease neuropathology in a cohort of elderly Norwegians.
A cohort of elderly Norwegians dying in nursing homes in the Oslo region have been genotyped for the Apolipoprotein E (ApoE) gene. Alzheimer's disease (AD) cortical neuropathology and clinical evidence of dementia were used to assign cases without evidence of other confounding neuropathology. Senile plaque (SP) and neurofibrillary tangle (NFT) densities in frontal, temporal and parietal cortex were then correlated with ApoE genotype to determine any relationship between ApoE genotype and AD pathology. Comparisons with ApoE epsilon 3, epsilon 4 and epsilon 2 allele dosage failed to show any significant effect on cortical SP densities in any cortical area. NFT densities were increased by epsilon 4 allele dosage in the frontal cortex but not in other cortical regions. A reduction was seen in cortical NFT densities with epsilon 2 allele, though again this was not consistently significant in any of the groups. The epsilon 3 allele failed to show any consistent effect on cortical NFT densities. Assessment by individual genotypes showed epsilon 2/3 < epsilon 2/4 < epsilon 3/3 < epsilon 3/4 < epsilon 4/4 which had highest cortical NFT densities in all areas. By genotype, SP densities were generally of the order epsilon 2/4 < epsilon 2/3 < epsilon 3/3 < epsilon 4/4 < epsilon 3/4 though in none of the groups was this significant. Duration of disease showed no consistent effect on neuropathological burden. ApoE genotype may have an effect on determining whether individuals suffer from AD and the age at onset of disease but may only have a minimal effect on pathology burden.
Aged↗
Oxidative damage to protein in sporadic motor neuron disease spinal cord.
The recent discovery that defects in the gene encoding copper-zinc superoxide dismutase (SOD1) are associated with some cases of familial motor neuron disease has heightened interest in the possibility that free radical mechanisms may contribute to selective motor neuron injury. Sporadic and familial motor neuron diseases are clinically and pathologically very similar and may share common pathophysiological mechanisms. Thus the role of free radical mechanisms as a contributory factor to motor neuron injury in the common sporadic form of motor neuron disease requires urgent exploration, particularly as this may provide an avenue for therapy aimed at retarding pathological progression. We investigated oxidative damage to proteins in the lumbar spinal cord by quantifying the protein carbonyl level from 19 patients with sporadic motor neuron disease, 8 neurologically normal control subjects, and 11 neurological disease control subjects, most of whom had slowly progressive neurodegenerative disease. In sporadic motor neuron disease the mean protein carbonyl level in the spinal cord was increased by 119% (p < 0.02) compared to normal control subjects and by 88% (p < 0.04) compared to the neurological disease control subjects. These data contribute to the emerging evidence that oxidative damage may play a contributory role in the neuronal death in sporadic motor neuron disease. This mechanism may be particularly important in a subset of patients with motor neuron disease.
Adult↗
CSF and plasma amino acid levels in motor neuron disease: elevation of CSF glutamate in a subset of patients.
Fasting plasma and/or CSF amino acid levels have been measured in a group of 37 patients with motor neurone disease (MND) and in 35 neurological control patients undergoing lumbar puncture prior to myelography. There were no significant differences in the plasma levels of 22 amino acids between the two groups. In CSF, there was a significant elevation of the glutamate level in the MND patients (P = 0.008). However, the MND group were heterogeneous with regard to CSF glutamate: 19/31 (61%) had levels within the normal range; eight (26%) had levels more than twice the upper limit of normal (> or = 10 mumol/l) and five (16%) had levels more than seven times normal (> or = 30 mumol/l). In a subset of seven MND patients there was a significant inverse correlation (rs = -0.775, P < 0.03) between CSF glutamate levels in life and the density of pre-synaptic glutamate re-uptake sites in the lumbar spinal cord measured in a post-mortem autoradiographic study. A possible interpretation of these findings is that an abnormality of glutamate transport may underlie the increase in CSF glutamate. The identification of a subgroup of MND patients with high CSF glutamate levels may be important in evaluating the clinical response to antiglutamate therapeutic agents.
Adult↗
Neutron activation analysis of trace elements in motor neuron disease spinal cord.
Levels of 10 trace elements were analysed in autopsied lumbar spinal cords of 38 motor neuron disease patients and 22 control subjects using instrumental neutron activation analysis. Statistically significant elevations of iron, selenium and zinc, and depletions of mercury and cesium were found in the spinal cords of motor neuron disease patients compared with control subjects. No significant correlations were found between disease duration, clinical severity or lumbar motor neuron counts and iron and selenium levels, suggesting that accumulation of these elements occur early as well as late in the disease process and therefore are not a consequence of end stage pathology. Increased iron in motor neuron disease spinal cord could act to enhance formation of reactive oxygen species. Our study supports the free radical hypothesis of neuron degeneration in motor neuron disease.
Adult↗
Effects of apolipoprotein E genotype on cortical neuropathology in senile dementia of the Lewy body and Alzheimer's disease.
Apolipoprotein E (APO E) genotypes were determined in a UK population of neuropathologically confirmed control cases, and in cases of Lewy body dementia (SDLT) and late onset Alzheimer's disease (AD). APO E epsilon 4 allele frequency was significantly elevated in both SDLT and AD groups with a concomitant reduction in the APO E epsilon 3 allele frequency. The epsilon 2 allele frequency in the AD group was only 25% of the control population, though because of the relatively small sample size this reduction was not significant; the epsilon 2 allele frequency in the SDLT group was normal. No significant association was found between senile plaque density and neurofibrillary tangle density in the neocortex and APO E allele dose in either SDLT or AD. Although the possession of APO E epsilon 4 is associated with an increased risk of developing SDLT and AD, actual APO E genotype does not appear to affect the burden of pathology.
Alleles↗
Parkinsonism in motor neuron disease: case report and literature review.
This report describes a patient who had clinical features of both motor neuron disease and Parkinson's disease. Neuropathological examination and immunocytochemical studies showed that he had motor neuron disease of the progressive muscular atrophy type, and Lewy body Parkinson's disease, with intracytoplasmic inclusion bodies characteristic of both conditions. This is the first detailed description of these two diseases occurring concurrently in the same patient. A review of all previously reported cases of combined motor neuron disease and parkinsonism has led to the following conclusions: (1) that these two neuropathologically defined diseases occur together very infrequently, but (2) that parkinsonism and substantia nigra degeneration are not uncommon as part of the multi-system disease process underlying motor neuron disease.
Aged↗