PubMed Health⌕ Search

Biomedical subjects

S E Daniel

Publications and source records attributed to S E Daniel.

At least 19 recordsLinked to original sources
PubMed1999

The tau gene A0 polymorphism in progressive supranuclear palsy and related neurodegenerative diseases.

Progressive supranuclear palsy is characterised pathologically by the deposition of neurofibrillary tangles consisting of tau protein. Patients with the disease have been reported to have a more frequent occurrence of one allele of an intronic polymorphism of the tau gene. Other diseases which may involve tau deposition include frontotemporal dementia and corticobasal degeneration. This polymorphism has been studied in a series of subjects with progressive supranuclear palsy, corticobasal degeneration, frontotemporal dementia, idiopathic Parkinson's disease, and normal controls to (1) confirm this association in a large series and (2) to investigate a possible role for this association in other disorders which involve tau deposition. The results confirm the finding of an overrepresentation of the A0 allele and the A0/A0 genotype in patients with progressive supranuclear palsy, in the largest series reported to date. The A0 allele was found in 91% of patients with progressive supranuclear palsy as opposed to 73% of controls (p<0.001) and the A0/A0 genotype was seen in 84% of patients as compared with 53% of controls (p<0.01). There was no significant difference between patients with Parkinson's disease, frontotemporal dementia, or corticobasal degeneration, and controls. The A0 allele may have a direct effect on tau isoform expression in progressive supranuclear palsy or it may be in linkage disequilibrium with an adjacent determinant of tau gene expression. The explanation for this difference between a predisposition factor to progressive supranuclear palsy and the other conditions may lie in the molecular pathology of these diseases.

Alleles↗
PubMed1998

Basal ganglia neuronal nitric oxide synthase mRNA expression in Parkinson's disease.

Expression of nitric oxide synthase (NOS) mRNA in post mortem brain was studied in putamen, globus pallidus and subthalamic nucleus (STN) of neurologically normal control subjects and patients with Parkinson's disease (PD) using in situ hybridization histochemistry. In PD, a significant increase in NOS mRNA expression was observed in the dorsal two-thirds of the STN with respect to the ventral one-third of the STN. A significant increase in NOS mRNA expression per cell in the medial medullary lamina of the globus pallidus was also observed in PD. NOS mRNA expression was significantly reduced in PD putamen. These findings provide evidence of increased activity of STN neurotransmitter systems in PD and demonstrate for the first time in any species that basal ganglia nitric oxide systems can be selectively regulated in response to changes in dopaminergic input.

Aged↗
PubMed1998

Glial pathology but absence of apoptotic nigral neurons in long-standing Parkinson's disease.

The cause and mechanism of neuronal cell death in the substantia nigra of patients with Parkinson's disease (PD) are unknown. There is also controversy about whether the cell death results from a single event followed by cell loss consistent with aging or whether there is an ongoing pathologic process. Using postmortem tissue obtained from the Parkinson's Disease Society Brain Tissue Bank in London, we have sought to establish whether apoptosis, or more specifically DNA fragmentation of neurons, is a prominent feature of nigral pathology. In addition, we have studied microglial activation in the substantia nigra as an indicator of ongoing pathology using the highly sensitive markers CR3/43 and EBM11. Reactive astrocytes have been assessed using immunostaining for glial fibrillary acidic protein (GFAP). Ten patients with pathologically proven PD were studied. In all cases, regardless of disease duration, severity, drug treatment, or age of the patient, there was no evidence of apoptosis in the substantia nigra as assessed by in situ end-labeling of DNA fragments using biotinylated dUTP and terminal deoxynucleotidyl transferase (TdT). In contrast, a case of multiple system atrophy (MSA) served as a positive control for the technique. In this case, positive DNA end-labeling could be found in neurons and non-neuronal cells in the brain stem. In the PD cases, there was, however, localized pathology in the substantia nigra as revealed by the CR3/ 43 and EBM11 markers for activated microglia. This process seemed independent of disease duration and was florid even in patients with severe neuronal loss. It remains to be determined to what extent the activation of glial cells reflects progressive nigral pathology, and whether those factors which are classically associated with prominent apoptotic neuronal cell death in vivo, such as neurotrophic factor deprivation, are prime causes of nigral neuronal loss in PD. Future studies should focus on recent-onset PD or incidental Lewy body disease to further address these questions.

Aged↗
PubMed1998

Conjugates of catecholamines with cysteine and GSH in Parkinson's disease: possible mechanisms of formation involving reactive oxygen species.

Oxidation of L-3,4-dihydroxyphenylalanine (L-DOPA) and dopamine (DA) to generate semiquinones/quinones, oxygen radicals, and other reactive oxygen species may play a role in neuronal cell death in Parkinson's disease (PD). In particular, semiquinones/quinones can form conjugates with thiol compounds such as GSH and cysteine. Exposure of L-DOPA, DA, and other catecholamines to a system generating O2.- radical led to O2(.-)-dependent depletion of added GSH (or cysteine), accompanied by the formation of thiol-DA or -DOPA adducts as detected by HPLC. Superoxide could additionally cause destruction of these adducts. Iron or copper ions could also promote conjugate formation between GSH or cysteine and DA and L-DOPA, especially if H2O2 was present. We applied HPLC to measure glutathionyl and cysteinyl conjugates of L-DOPA, DA, and 3,4-dihydroxyphenylacetic acid (DOPAC) in postmortem brain samples from PD patients and normal control subjects. Conjugates were detected in most brain areas examined, but levels were highest in the substantia nigra and putamen. In most regions, adduct levels were lower in PD, but there were significant increases in cysteinyl adducts of L-DOPA, DA, and DOPAC in PD substantia nigra, suggesting that acceleration of L-DOPA/DA oxidation occurs in PD, although we cannot say if this is a primary feature of the disease or if it is related to therapy with L-DOPA. In vitro, conjugate formation could be inhibited by the dithiol dihydrolipoate but not by its oxidised form, lipoic acid.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1998

Frontal cortical synaptophysin in Lewy body diseases: relation to Alzheimer's disease and dementia.

OBJECTIVES: Dementia in Alzheimer's disease correlates closely with loss of neocortical synapses. Similar synaptic loss has been shown in patients whose Alzheimer's disease is also associated with neocortical and brain stem Lewy bodies. The aim was to determine if dementia in Lewy body disease was associated with diminished concentrations of midfrontal cortex synaptophysin. METHODS: An immunobinding assay was used to measure synaptophysin in postmortem samples of midfrontal cortex from 89 patients with Alzheimer's disease (ages 59-100, mean 79), 22 with combined Lewy body disease and Alzheimer's disease (ages 69-103, mean 79), 15 demented patients with "pure" Lewy body disease (ages 57-80, mean 74), nine with neocortical and brain stem Lewy bodies who had Parkinson's disease but were not demented (ages 68-85, mean 79), and 20 neurologically normal controls (ages 58-89, mean 75). The diagnosis was confirmed in all cases by detailed neuropathological examination of the contralateral hemibrain. Seven of the patients in the pure Lewy body disease with dementia group had initially presented with parkinsonism and eight with dementia. RESULTS: Synaptophysin concentrations (arbitrary units (AU)/microg) in patients with Alzheimer's disease (mean 79 (SD 28)) or combined Lewy body disease and Alzheimer's disease (mean 83 (SD 33)) were significantly lower than in controls (mean 115 (SD 29)) (p=0.002). Synaptophysin concentrations in demented patients with pure Lewy body disease (mean 106 SD 39) and patients with Lewy body disease who were not demented (mean 101 (SD 18)) did not differ significantly from control values or from each other. CONCLUSION: Loss of midfrontal cortex synapses probably contributes to dementia in Lewy body disease when Alzheimer's disease is also present but not to the dementia of pure Lewy body disease.

Aged↗
PubMed1998

Clinical usefulness of magnetic resonance imaging in multiple system atrophy.

OBJECTIVES: To determine the sensitivity, specificity, and positive predictive values of a selection of abnormal findings in the putamen and infratentorial structures on routine magnetic resonance imaging for distinguishing between multiple system atrophy, idiopathic Parkinson's disease, and age matched controls. PATIENTS AND METHODS: Two neuroradiologists blindly and independently rated axial T2 weighted and proton density MRI of 44 patients with multiple system atrophy, 47 patients with idiopathic Parkinson's disease, and 45 controls. High field (1.5 T) scans were available in 16 patients with multiple system atrophy, 15 patients with idiopathic Parkinson's disease, and 16 controls. All other patients had 0.5 T scans. RESULTS: On both 0.5 and 1.5 T scans the following items had high specificity but low sensitivity: putaminal atrophy, a hyperintense putaminal rim, and infratentorial signal change. Finding any infratentorial abnormality gave higher sensitivity but lower specificity. Putaminal isointensity or hypointensity relative to globus pallidus, absolute putaminal hypointensity, and altered size of the olives were not useful discriminators. The overall sensitivity was 73% on 0.5 T and 88% on 1.5 T scans. The specificities of these findings for multiple system atrophy in comparison to idiopathic Parkinson's disease and controls on 0.5 T were 95% and 100% respectively, and on 1.5 T were 93% and 91% respectively. Finding any of the described abnormalities on MRI gave a positive predictive value of 93% on the 0.5 T machine, and 85% on the 1.5 T scanner.

Adult↗
PubMed1997

Upregulation of the anti-apoptotic protein Bcl-2 may be an early event in neurodegeneration: studies on Parkinson's and incidental Lewy body disease.

Apoptosis and oxidative stress have been suggested to be involved in Parkinson's disease (PD). However, whether this is a cause or consequence of neurodegeneration is unknown. Incidental Lewy Body disease (ILBD) appears to be a presymptomatic form of Parkinson's disease where individuals are neurologically normal, but after post-mortem examination pathology similar to Parkinson's disease is present. Thus, ILBD can be used to examine the early stages of the pathological process in PD. We investigated the levels of Bcl-2, an anti-apoptotic protein known to decrease cell death induced by several mechanisms, including oxidative stress. Our data show that Bcl-2 is significantly raised in the basal ganglia regions of PD patients as compared to age-matched controls. A similar trend is also found in ILBD. We propose that Bcl-2 increases in some brain regions as an early event and that these brain regions are under a stress for perhaps many years before any symptomatic changes occur.

Age Factors↗
PubMed1997

Tau protein in the glial cytoplasmic inclusions of multiple system atrophy can be distinguished from abnormal tau in Alzheimer's disease.

The glial cytoplasmic inclusion (GCI) is a histological hallmark for multiple system atrophy (MSA). These inclusions are in oligodendrocytes, contain microtubular structures of 20-30 nm diameter, and can be labelled immunohistochemically with antibodies to ubiquitin, alphaB-crystallin, alpha- and beta-tubulin, and the microtubule-associated protein tau. GCIs have been compared with neuronal inclusions in other neurodegenerative disorders including the neurofibrillary tangles (NFTs) found in Alzheimer's disease (AD), which also contain tau protein. In order to determine whether the tau protein of GCIs in MSA is similar to that observed in AD we used a panel of antibodies to phosphorylation-independent (SMI51, TP007, TP70), dephosphorylation-dependent (Tau.1), and phosphorylation-dependent antibodies to tau and neurofilaments (AT8, AT180, AT270, SMI31, SMI34, RT97, BF10, 8D8). Immunohistochemistry was performed on paraffin wax-embedded brain tissue of the cerebellum, brainstem, and frontal lobes (Brodmann areas 4/6) of ten clinically and neuropathologically well-characterised cases of MSA, two cases of AD, and two normal controls. The NFTs of the AD cases were labelled with all the phosphorylation-dependent and phosphorylation-independent antibodies and with Tau.1 only after treatment with alkaline phosphatase. In contrast, GCIs were immunolabelled by the phosphorylation-independent antibodies and Tau.1, but not by the phosphorylation-dependent antibodies. These data demonstrate that the tau in GCIs is different from the abnormally phosphorylated tau found in AD and is similar to normal adult tau. The mechanism causing the abnormal accumulation of tau in GCIs remains to be elucidated.

Adult↗
PubMed1997

Apolipoprotein E e4 allele frequency in patients with multiple system atrophy.

The glial cytoplasmic inclusion provides a histological hallmark for multiple system atrophy, a group of neurodegenerative disorders including: striatonigral degeneration, olivopontocerebellar atrophy, and Shy-Drager syndrome. Apolipoprotein E (APOE) genotype was determined by the polymerase chain reaction and restriction digestion of DNA extracted from frozen brain tissue from 22 patients (64.9 +/- 2.2 years) with clinically and neuropathologically verified multiple system atrophy (MSA). In addition, brain tissue from 36 age- and sex-matched patients who died with Alzheimer's disease (68.8 +/- 1.6 years) and 66 neurologically and psychiatrically normal subjects (66.6 +/- 1.8 years) was genotyped. The APOE e4 allele frequency in the Alzheimer's disease subjects was significantly increased (0.44, P < 0.001), as has been reported previously. The APOE e4 allele frequency of the MSA cases (0.11) was not significantly different from that of the control subjects (0.12). These data indicate that the APOE e4 allele is not a risk factor for multiple system atrophy.

Aged↗
PubMed1997

Multiple system atrophy: a review of 203 pathologically proven cases.

We report the clinicopathological features of 203 cases of pathologically proven multiple system atrophy (MSA) from 108 publications up to February 1995. The majority of patients showed symptoms in their early fifties, and men were more commonly affected than women (ratio of 1.3:1). Most patients suffered from some degree of autonomic failure (74%). Parkinsonism was the most common motor disorder (87%), followed by cerebellar ataxia (54%) and pyramidal signs (49%). The response to levodopa was poor in most patients, but there was a subgroup with a good response, who also often developed axial levodopa-induced dyskinesias. Other characteristic features included severe dysarthria, stridor, and, in a few patients, contractures and dystonia (antecollis). Mild or moderate intellectual impairment occurred in some cases, but severe dementing illness was most unusual. The main pathological change comprised cell loss and gliosis in the putamen, caudate nucleus, external pallidum, substantia nigra, locus ceruleus, inferior olives, pontine nuclei, cerebellar Purkinje cells, and intermediolateral cell columns of the spinal cord. However, other neuronal populations were also involved to varying degrees, such as the thalamus, vestibular nucleus, dorsal vagal nucleus, corticospinal tracts, and anterior horn cells. Characteristic glial and/or neuronal cytoplasmic inclusions were identified in all cases in which they were sought, irrespective of clinical presentation. Akinesia correlated with the degree of nigral and putaminal cell loss, whereas rigidity was related only to the later. Tremor was unrelated to cell loss at any site. Ataxia correlated with the degree of olivopontocerebellar atrophy. Pyramidal signs were associated with pyramidal tract pallor. Our analysis also confirmed an association of postural hypotension with intermediolateral cell column degeneration.

Aged↗
PubMed1997

Mitochondrial respiratory chain function in multiple system atrophy.

Multiple system atrophy (MSA) is a clinico-pathological entity distinct from idiopathic Parkinson's disease (PD) that is responsible for 5-10% of cases of parkinsonism. Degeneration of nigral neurones is a feature of both diseases. A specific deficiency of mitochondrial complex I activity has been found in PD substantia nigra. We have analysed mitochondrial function in substantia nigra and platelets from MSA patients to identify any respiratory chain defect in this disorder and to determine its tissue specificity. As our MSA patients had been on L-DOPA, we also sought to establish whether this treatment could cause the complex I defect as seen in PD. We found no significant difference in respiratory chain activity corrected for mitochondrial mass between control and MSA patients in either of the tissues studied. These results provide a biochemical dimension to the differences between MSA and idiopathic PD. In addition, the fact that L-DOPA failed to induce a complex I defect in MSA substantia nigra suggests that this treatment is unlikely to cause the complex I deficiency in PD, without additional factors that may operate in PD.

Aged↗
PubMed1997

Amyloid beta-peptide and its relationship with dementia in Lewy body disease.

Cerebral cortical Lewy bodies occur in a spectrum of clinical syndromes including Parkinson's disease (PD) with and without dementia, and dementing conditions clinically resembling Alzheimer's disease with few or without parkinsonian features. It is unclear whether these conditions are variants of one disease process or represent pathogenetically distinct entities. Here we compared the cortical pathology in post mortem brains of three groups representing the predominant clinical phenotypes of Lewy body disease, including 27 non-demented cases of PD, 23 demented PD cases, and 11 cases of Lewy body disease who initially presented with dementia and showed only limited features of parkinsonism during the course of their illness. In addition to neuropathology, computer-assisted histoblot analysis was used to assess cortical amyloid beta-peptide deposition. There was wide overlap of the pathomorphometric features between the two groups of demented cases. It appears that substantial cortical Alzheimer-type pathology present in most demented cases contributes significantly to the development of dementia in Lewy body disease.

Aged↗
PubMed1997

Mitochondrial DNA polymorphisms in pathologically proven Parkinson's disease.

To date, five single base pair changes of the mitochondrial DNA have been reported to occur either exclusively or with increased frequency in Caucasian patients with Parkinson's disease (PD) and it has been postulated that these mutations might be casually related to the observed inhibition of mitochondrial respiratory chain function in PD. To evaluate these findings, we analysed the frequency of all five polymorphisms in 100 cases of pathologically proven cases of PD. We were either unable to detect the previously described polymorphisms in our series or found them to be present with the same frequency among controls. Our data do not support the hypothesis of an involvement of the mitochondrial DNA in the pathogenesis of PD.

Adult↗
PubMed1997

Oxidative DNA damage in the parkinsonian brain: an apparent selective increase in 8-hydroxyguanine levels in substantia nigra.

Oxidative damage has been implicated in the pathology of Parkinson's disease (PD), e.g., rises in the level of the DNA damage product, 8-hydroxy-2'-deoxyguanosine, have been reported. However, many other products result from oxidative DNA damage, and the pattern of products can be diagnostic of the oxidizing species. Gas chromatography/mass spectrometry was used to examine products of oxidation and deamination of all four DNA bases in control and PD brains. Products were detected in all brain regions examined, both normal and PD. Analysis showed that levels of 8-hydroxyguanine (8-OHG) tended to be elevated and levels of 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FAPy guanine) tended to be decreased in PD. The most striking difference was a rise in 8-OHG in PD substantia nigra (p = 0.0002); rises in other base oxidation/deamination products were not evident, showing that elevation in 8-OHG is unlikely to be due to peroxynitrite (ONOO-) or hydroxyl radicals (OH.), or to be a prooxidant effect of treatment with L-Dopa. However, some or all of the rise in 8-OHG could be due to a change in 8-OHG/FAPy guanine ratios rather than to an increase in total oxidative guanine damage.

Aged↗
PubMed1997

A generalised increase in protein carbonyls in the brain in Parkinson's but not incidental Lewy body disease.

The degeneration of neurones in Parkinson's disease (PD) may involve oxidative stress. Previously, increased lipid peroxidation and oxidative DNA damage have been reported in parkinsonian substantia nigra. In the present study the protein carbonyl assay was used to assess oxidative protein damage in postmortem brain tissue from patients with PD and age-matched controls. In brain areas associated with PD, such as substantia nigra, caudate nucleus, and putamen, there was a significant increase in carbonyl levels. However, increased carbonyl levels were also found in areas of the brain not thought to be affected in PD. This perhaps suggests that protein carbonyl formation is related to therapy with L-DOPA, which can exert prooxidant properties in vitro. Consistent with this possibility, brain regions from individuals with incidental Lewy body disease (putative presymptomatic PD) showed no rise in carbonyls in any brain areas. Our data show that either oxidative protein damage occurs widely but late in PD brain, and/or that L-DOPA treatment contributes to protein oxidation.

Adult↗
PubMed1997

Olfactory dysfunction in Parkinson's disease.

OBJECTIVE: To evaluate olfactory function in Parkinson's disease. METHODS: A standardised odour identification test was used, together with an evoked potential assessment with hydrogen sulphide. In addition, histological analysis was performed on the olfactory bulbs of cadavers who died from Parkinson's disease. RESULTS: Over 70% of patients studied (71 of 96) were outside the 95% limit of normal on the identification test in an age matched sample and there was an unusual pattern of selective loss to certain odours, not hitherto described. The evoked potentials were significantly delayed but of comparable amplitude to a control matched population. Of the 73 patients studied only 37 had a technically satisfactory record containing a clear response to both gases and of these, 12 were delayed. For H2S there was more delay on stimulating the right nostril than the left. Some patients with normal smell identification test scores had delayed evoked potentials. In the pathological examination of olfactory bulbs from eight brains, changes characteristic of Parkinson's disease (Lewy bodies) were seen in every olfactory bulb, particularly in the anterior olfactory nucleus, and were sufficiently distinct to allow a presumptive diagnosis of Parkinson's disease. CONCLUSIONS: Olfactory damage in Parkinson's disease is consistent and severe and may provide an important clue to the aetiology of the disease.

Adolescent↗
PubMed1997

Neuronal loss and plasticity in the supraoptic nucleus in Parkinson's disease.

Disturbed circadian control of renal water excretion and blood pressure adaptation in Parkinson's disease (PD) suggest impaired hypothalamic magnocellular neurosecretion. To test the hypothesis that this may relate to specific hypothalamic pathology in PD, we studied morphometrically the neuronal population of the supraoptic nucleus (SON) in PD patients and controls. Neuronal loss in the SON of PD patients was associated with increased somatic, nuclear, and nucleolar size of remaining neurons, suggesting compensatory response of these cells. We conclude that SON pathology is a feature of PD and may account for specific signs of neurohumoral dysfunction.

Aged↗