Biomedical subjects

A J Harding

Publications and source records attributed to A J Harding.

At least 19 recordsLinked to original sources

PubMed2002

Visual hallucinations in Lewy body disease relate to Lewy bodies in the temporal lobe.

Consensus opinion characterizes dementia with Lewy bodies (DLB) as a progressive dementing illness, with significant fluctuations in cognition, visual hallucinations and/or parkinsonism. When parkinsonism is an early dominant feature, consensus opinion recommends that dementia within the first year is necessary for a diagnosis of DLB. If dementia occurs later, a diagnosis of Parkinson's disease with dementia (PDD) is recommended. While many previous studies have correlated the neuropathology in DLB with dementia and parkinsonism, few have analysed the relationship between fluctuating cognition and/or well-formed visual hallucinations and the underlying neuropathology in DLB and PDD. The aim of the present study was to determine any relationship between these less-studied core clinical features of DLB, and the distribution and density of cortical Lewy bodies (LB). The brains of 63 cases with LB were obtained over 6 years following population-based studies of dementia and parkinsonian syndromes. Annual, internationally standardized, clinical assessment batteries were reviewed to determine the presence and onset of the core clinical features of DLB. The maximal density of LB, plaques and tangles in the amygdala, parahippocampal, anterior cingulate, superior frontal, inferior temporal, inferior parietal and visual cortices were determined. Current clinicopathological diagnostic criteria were used to classify cases into DLB (n = 29), PDD (n = 18) or parkinsonism without dementia (n = 16) groups. Predictive statistics were used to ascertain whether fluctuating cognition or visual hallucinations predicted the clinicopathological group. Analysis of variance and regressions were used to identify any significant relationship(s) between the presence and severity of neuropathological and clinical features. Cognitive fluctuations and/or visual hallucinations were not good predictors of DLB in pathologically proven patients, although the absence of these features early in the disease course was highly predictive of PDD. Cases with DLB had higher LB densities in the inferior temporal cortex than cases with PDD. There was no association across groups between any neuropathological variable and the presence or absence of fluctuating cognition. However, there was a striking association between the distribution of temporal lobe LB and well-formed visual hallucinations. Cases with well-formed visual hallucinations had high densities of LB in the amygdala and parahippocampus, with early hallucinations relating to higher densities in parahippocampal and inferior temporal cortices. These temporal regions have previously been associated with visual hallucinations in other disorders. Thus, our results suggest that the distribution of temporal lobe LB is more related to the presence and duration of visual hallucinations in cases with LB than to the presence, severity or duration of dementia.

Adult↗

PubMed2002

Patients with vascular dementia due to microvascular pathology have significant hippocampal neuronal loss.

BACKGROUND: Alzheimer's disease (AD) is characterised by functional impairment, cerebral atrophy, and degeneration of specific neuronal populations, especially pyramidal neurones of the cerebral cortex and hippocampal formation. Although patients with subcortical vascular dementia have been shown to have similar metabolic and volumetric deficits to those with AD, the underlying pathogenesis of these changes is poorly understood. OBJECTIVE: To determine whether pyramidal cell loss occurs in small vessel disease (SVD) dementia by quantifying hippocampal volume and CA1 neurone number. METHODS: Fifty four prospectively studied patients with dementia were screened, and four patients fulfilling criteria for SVD with no other significant neuropathological abnormality were identified. These were compared with five patients fulfilling criteria for AD and seven controls matched for age and sex. The hippocampal formation was serially sectioned, and the number of CA1 pyramidal neurones estimated using the optical dissector technique. Analysis of variance was used to evaluate group differences. RESULTS: Patients in both the AD and SVD groups showed a substantial loss of pyramidal neurones from the CA1 region. The pattern of hippocampal atrophy and the degree of CA1 neuronal loss were similar in the two dementia groups. CONCLUSIONS: These findings support recent in vivo studies showing similar metabolic deficits and atrophy in AD and subcortical vascular dementia. In addition, they provide evidence that the underlying cause of these abnormalities is a similar loss of neurones. Whereas the cause of the neuronal loss in AD is related to the deposition of abnormal proteins, the cause in SVD is unknown. In the absence of other pathologies, damage to cerebral microvasculature should be considered a likely candidate.

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PubMed2001

Cortical Lewy body pathology in the diagnosis of dementia.

Dementia with Lewy bodies (DLB) and Parkinson's disease (PD) are distinguishable clinically but often not neuropathologically. This study aims to test whether the distribution of cortical Lewy bodies differs in these clinicopathological groups and to develop diagnostic protocols for their differentiation. Brains were obtained at autopsy from cases recruited from prospective clinical studies of dementia or movement disorders. All cases with significant pathologies other than Lewy bodies or plaques were excluded. Cases were categorised into either PD without dementia, DLB (dementia first or within 2 years of disease onset), or PD with a later onset of dementia (PDD). The distribution and density of Lewy bodies and Lewy neurites was determined using antibodies to ubiquitin and alpha-synuclein. Cortical Lewy body densities could not separate cases of DLB from those with PDD. However, semiquantitative thresholds in the parahippocampus could separate demented from non-demented cases with high sensitivity and specificity. Interactions between multiple pathologies were determined using factor analysis. Although many cases had CA2 Lewy neurites, this was not associated with severity or duration of either dementia or parkinsonism. Most DLB cases had significant plaque pathology, and severity and duration of dementia was related to both increasing parahippocampal Lewy body densities and neuritic plaque grade. Weighted kappa statistics revealed that the combination of these pathologies indicated a more severe dementia. These results suggest that dual pathologies cause DLB, and high densities of parahippocampal Lewy bodies indicate dementia regardless of additional pathologies.

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PubMed2000

Cortical inflammation in Alzheimer disease but not dementia with Lewy bodies.

BACKGROUND: There have been no previous studies on the role of inflammation in the brain for the second most common dementing disorder, dementia with Lewy bodies. OBJECTIVE: To investigate the degree of cortical inflammation in dementia with Lewy bodies (DLB) compared with Alzheimer disease (AD) and control brains. DESIGN AND MAIN OUTCOME MEASURES: Post-mortem tissue collection from a brain donor program using standardized diagnostic criteria. Brains collected from January 1, 1993, through December 31, 1996, were screened and selected only for the presence or absence of tau neuritic plaques. Results of immunohistochemistry for HLA-DR were quantified using area fraction counts. Counts were performed by investigators who were unaware of the diagnosis. Results were compared across groups using analysis of variance and posthoc testing. SETTING: A medical research institute in Sydney, Australia. PATIENTS: Eight brains with DLB and without the tau neuritic plaques typical of AD, 10 brains with AD and no Lewy bodies, and 11 nondemented controls without significant neuropathological features were selected from a consecutive sample. RESULTS: Compared with AD, DLB demonstrated significantly less inflammation in the form of HLA-DR-reactive microglia in all cortical regions (P<.001, posthoc). The level of inflammation in DLB was comparable to that seen in controls (P=.54, post hoc). CONCLUSIONS: Inflammation appears related to the tau neuritic plaques of AD. Despite similar clinical presentations, therapeutic anti-inflammatory strategies are not likely to be effective for pure DLB. Arch Neurol. 2000.

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PubMed2000

Practical measures to simplify the Braak tangle staging method for routine pathological screening.

The examination of neurofibrillary tangles is now recommended for the diagnosis of Alzheimer's disease as their location and density can distinguish early, intermediate and late disease stages. While the Braak tangle staging protocol can identify these stages, it uses an uncommon silver stain and hippocampal sample. The present study evaluates the Braak protocol using commonly used methods and cases fulfilling either CERAD criteria for Alzheimer's disease, criteria for dementia with Lewy bodies or without neurological disease. Temporal and occipital cortices from 72 cases were stained using tau immunohistochemistry and the Gallyas and modified Bielschowsky silver stains. The modified Bielschowsky silver stain was equivalent to the Gallyas silver stain for tangle staging. Semiquantitative evaluation of neurofibrillary tangles in the hippocampus and the inferior temporal cortex provided equivalent information to that obtained using the original Braak tangle staging protocol (kappa statistic of 0.97). Comparison of this modification with the CERAD criteria provided moderate agreement (0.51) between diagnostic categories when cases with dementia with Lewy bodies were included, but substantially increased agreement (0.74) when they were excluded. This simplification of the Braak tangle staging protocol is easy to apply, can be readily incorporated into existing CERAD procedures, and helps to distinguish cases with neurofibrillary tangles from those with Lewy bodies.

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PubMed2000

Regional brain atrophy in progressive supranuclear palsy and Lewy body disease.

There have been no previous three-dimensional volumetric studies of regional brain atrophy in patients with pathologically confirmed progressive supranuclear palsy (PSP). Postmortem cortical and subcortical volumes were compared with neuropathology in 9 patients with PSP, 15 patients with Parkinson's disease, 10 patients with dementia with Lewy bodies, and 23 controls. Cases with the neuritic pathology of Alzheimer's disease were excluded. The topography of brain atrophy differed according to clinicopathological phenotype. Patients with Parkinson's disease had atrophy confined to the amygdala. Atrophy of the frontal lobe was found in both PSP and dementia with Lewy bodies and correlated with increasing neurofibrillary tangle or Lewy body densities, respectively. Patients with PSP could be differentiated by their marked atrophy of the internal globus pallidus. Further analysis of variance revealed that trends for greater frontal lobe atrophy correlated with clinical dementia in PSP, whereas both greater frontal and hippocampal atrophy and higher densities of Lewy bodies and Lewy neurites correlated with clinical dementia in cases with Lewy bodies. The present study provides evidence for selective regional atrophy that correlates with the underlying pathology of PSP and Lewy body disease.

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PubMed1999

Neuronal loss in functional zones of the cerebellum of chronic alcoholics with and without Wernicke's encephalopathy.

This study examines the effect of chronic alcohol consumption on the human cerebellum using operational criteria for case selection [Caine D. et al. (1997) J. Neurol. Neurosurg. Psychiat. 62, 51-60] and unbiased stereological techniques. We describe, for the first time, structural changes in different functional zones of the cerebellum of chronic alcoholics and correlate these changes with specific clinical symptoms. No consistent changes in the number of neurons or the structural volume for any cerebellar region were observed in the chronic alcoholics without the clinical signs of Wernicke's encephalopathy. In all cerebellar measures, these chronic alcoholics did not differ significantly from the non-alcoholic controls, suggesting that chronic alcohol consumption per se does not necessarily damage human cerebellar tissue. However, several cerebellar changes were noted in the thiamine-deficient alcoholics studied. There was a significant decrease in Purkinje cell density (reduced on average by 43%) and molecular layer volume (reduced by 32%) in the cerebellar vermis in all thiamine-deficient chronic alcoholics. A decrease in cell density and atrophy of the molecular layer, where the dendritic trees of the Purkinje cells are found, without significant cell loss suggests loss of cellular dendritic structure and volume. These thiamine-deficient alcoholics also had a significant decrease (36% loss) in the estimated Purkinje cell number of the flocculi, disrupting vestibulocerebellar pathways. These results indicate that cerebellar Purkinje cells are selectively vulnerable to thiamine deficiency. There is evidence that this damage contributes significantly to the clinical signs of Wernicke's encephalopathy. There was a 36% loss of Purkinje cells in the lateral lobe in alcoholics with mental state signs and 42% atrophy of vermal white matter in ataxic alcoholics. The finding of a 57% loss of Purkinje cells and a 43% atrophy of the molecular layer of the vermis in alcoholics with cerebellar dysfunction supports previous findings highlighting the importance of spinocerebellar pathways to these symptoms.

Adult↗

PubMed1998

Simplified neuropathological diagnosis of dementia with Lewy bodies.

Pathological criteria have recently been developed to differentiate those cases where Lewy bodies contribute to the dementing process. We applied consensus criteria to 20 cases with a pathological diagnosis of Alzheimer's disease (all demented) and/or Parkinson's disease (three without dementia) and eight controls. In addition, we applied the criteria to the different cortical layers to determine whether the site of the semiquantification affected the diagnosis. In the parietal lobe, few Lewy bodies were observed, and this region could be excluded. Rare Lewy bodies present in the frontal association cortex in a number of Parkinson's disease cases resulted in their classification as limbic or transitional cases with Lewy bodies. Exclusion of this non-limbic association cortex resulted in many of these cases with rare cortical Lewy bodies being re-classified as having brain stem predominant Lewy bodies, thus improving the diagnostic accuracy of the criteria. Most of these cases were non-demented. No other case was re-classified by excluding these cortical regions from the analysis. Few Lewy bodies were present in cortical layers I and II, and these layers could be excluded from the semiquantitative procedure without change to the overall classification of cases. The occasional presence of possible Lewy bodies in cases with Alzheimer's disease and controls incorrectly classified these cases as having brain stem predominant Lewy body disease, although these cases had no brain stem Lewy bodies. These modifications to the consensus criteria for assessing Lewy body disease (i.e. exclude parietal and frontal lobe, cortical layers I and II, and cases without brain stem Lewy bodies), provide significant time and cost savings for neuropathologists and researchers using this criteria to diagnose and study dementia with Lewy bodies.

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PubMed1998

Variation in hippocampal neuron number with age and brain volume.

Hippocampal size and neuron number are reduced in a number of conditions, including temporal lobe epilepsy and Alzheimer's disease. Furthermore, a decrease with advancing age has also been suggested. The present study examined the entire hippocampal formation of 12 subjects aged from 46 to 85 years and free from neurological disease. The volume of seven subregions (CA1, CA2-3, CA4, dentate gyrus, subiculum, presubiculum and white matter) was determined and the number of neurons estimated in each of these grey matter subregions using the optical dissector technique. There was a significant relationship between CA1 neuron number and cerebrum volume. Multivariate analysis showed the greater contribution to the variance in CA1 neuron number was made by cerebrum volume (69%) rather than age (2%) or sex (1%). The findings of this study show that, in neurologically normal individuals, brain size is a major determinant of the number of CA1 neurons.

Age Distribution↗

PubMed1997

Chronic alcohol consumption does not cause hippocampal neuron loss in humans.

High alcohol consumption for long periods of time causes significant hippocampal neurodegeneration in rodents. A single study using neuronal density measures has reported similar findings in humans. The present study aims to substantiate these findings in human alcoholics using unbiased stereological techniques. Both amnesic (n = 5) and nonamnesic (n = 7) chronic alcoholics were selected and compared with nonalcoholic controls (n = 8) and patients with marked memory loss and hippocampal neurodegeneration caused by Alzheimer's disease (n = 4). Hippocampal volume was significantly reduced in the alcoholics and in patients with Alzheimer's disease. However, in alcoholics the volume reduction occurred exclusively in the white matter, whereas both the gray and white matter were reduced in the patients with Alzheimer's disease. Neuron loss occurred exclusively from the CA1 and subiculum subregions of the hippocampus in Alzheimer's disease. No neuron loss occurred from any subregion of the hippocampus in alcoholics. There were no correlations with age and any of the volume or neuron number measures. Hippocampal volume correlated with brain volume and with the regional gray and white matter volumes within the hippocampus. In addition, hippocampal gray matter volume correlated with the number of CA1 pyramidal neurons. These results do not support the theory that chronic alcohol consumption is neurotoxic to hippocampal pyramidal neurons in humans. Further, the present results suggest that changes observed in rodent models of alcoholism do not parallel those observed in humans, questioning the validity of such models.

Aged↗

PubMed1997

Increased c-fos expression in the brain during experimental murine cerebral malaria: possible association with neurologic complications.

Cerebral expression of c-fos protein was studied by immunocytochemistry in murine cerebral malaria (CM) and malaria without cerebral involvement (non-CM). c-fos expression, low in the brains of uninfected mice, increased in frequency, intensity, and distribution during the course of fatal CM (e.g., a 70-fold increase on day 7 after inoculation). These changes paralleled the timing and degree of the neurologic complications and histopathologic changes. Only a slight increase in c-fos expression was detectable in non-CM mice on day 7 after inoculation. Dexamethasone treatment (days 0 and 1 after inoculation) of the CM mice largely prevented the increased cerebral c-fos expression, histopathologic changes, cerebral complications, and death. Increased c-fos expression may indicate the specific neuronal pathways activated by the immunopathologic process of fatal murine CM and could be associated with the behavioral changes and neurologic complications in this model.

Animals↗

PubMed1996

High-performance liquid chromatography method with light-scattering detection for measurements of lipid class composition: analysis of brains from alcoholics.

A high-performance liquid chromatographic method with evaporative light-scattering detection was developed for the analysis of intact lipid classes in nervous tissue. The method had the ability to resolve plasmalogen-phosphatidyl-ethanolamine and diacyl-phosphatidylethanolamine along with other major phospholipid classes in a single run. This technique was employed for the investigation of the effects of chronic alcohol consumption on the membrane lipid class composition of human brains (alcoholics, n = 13; controls, n = 11). Measurements were performed on cholesterol, cerebrosides, sulfatides, phospholipids and sphingolipids in total lipid extracts of white matter, gray matter and cerebellar regions of human brains. No significant differences in the lipid class composition between the groups were observed.

Alcoholism↗

PubMed1996

Glial fibrillary acidic protein (GFAP) immunohistochemistry in human cortex: a quantitative study using different antisera.

Glial fibrillary acidic protein (GFAP) is the principal marker for brain astrocytes. The present study aims to examine the variability in GFAP immunohistochemistry in formalin-fixed human brain. Four commercially-available antisera were tested using standardised protocols in the cerebral cortex of three cases with prominent glial reactions and one control. GFAP immunoreactivity was largely confined to the pial surface and white matter in control cortex, with the number of astrocytic cell bodies and processes as well as intensity of staining markedly increased in damaged cortices. A dramatic difference in the pattern of GFAP staining using different antisera was observed and may account for discrepancies between past studies. This variance has important practical implications for the interpretation of results using GFAP immunohistochemistry in human tissue.

Alzheimer Disease↗

PubMed1996

Loss of vasopressin-immunoreactive neurons in alcoholics is dose-related and time-dependent.

The chronic consumption of alcohol significantly reduces the number of vasopressin-producing neurons in the rat supraoptic nucleus [Maderia et al. (1993) Neourscience 56, 657-672] suggesting this region is particularly vulnerable to alcohol neurotoxicity. As hypothalamic vasopressin producing neurons are necessary for fluid homeostasis, it is important to assess if similar changes occur in humans. We analysed arginine vasopressin-immunoreactive neurons in the magnocellular hypothalamic nuclei of ten chronic alcoholic men (consuming > 80 g of ethanol per day) and four age- and sex-matched controls (consuming < 10g of ethanol per day). Brains were collected at autopsy and fixed in formalin. Serial 50 mu m-thick-sections of the hypothalamus were stained and assessed. The volume of the paraventricular and supraoptic nuclei and number of neurons were estimated using Cavalieri's principle and the optical dissector technique. The volume of these nuclei significantly correlated with the number of neurons and the number of vasopressin-immunoreactive neurons, and these measures significantly correlated with the maximum daily intake of alcohol. There was a loss of neurons at consumption levels greater than 100 g of ethanol per day, principally affecting the supraoptic nucleus although neuron loss also occurred in the paraventricular nucleus in cases with long histories of alcohol consumption. These results indicate that chronic alcohol consumption is toxic to hypothalamic vasopressin-producing neurons in a concentration- and time-dependent manner. As these magnocellular neurons are osmo-receptive, neuronal loss may result in fluid imbalances.

Adult↗

PubMed1995

Effect of L-10B-p-boronophenylalanine-fructose and the boron neutron capture reaction on mouse brain dopaminergic neurons.

Radiation damage to the dopamine tracts caused by enriched L-10B-p-boronophenylalanine (L-10BPA)-fructose and the boron neutron capture reaction was investigated using the mouse model. Following various treatments with L-10BPA and neutron irradiation of the head, the brain was perfusion fixed and removed; 50-microns frozen sections were cut. Dopaminergic neurons were visualized using immunohistochemistry for tyrosine hydroxylase. The administration of L-10BPA had no permanent effect on dopaminergic tracts. Neutron capture therapy with L-10BPA caused a reduction in tyrosine hydroxylase immunohistochemical activity within 4 h of irradiation, but by 48 h, this reduction reversed. No damage was observed at 120 h postirradiation.

Animals↗

PubMed1995

Comparison of the number of vasopressin-producing hypothalamic neurons in rats and humans.

The aim of this study was to assess the number and proportion of vasopressin-producing neurons in the hypothalamic magnocellular nuclei in rats and humans. Accurate and unbiased neuronal counts were estimated using the optical disector method. Arginine vasopressin-containing neurons were immunohistochemically visualized in formalin-fixed tissue sections. The magnocellular neurons were similar in size and morphology in both species. While the human hypothalamus contained significantly more vasopressin-containing neurons compared with the rat (36-fold increase), the proportion of vasopressin-containing neurons between species was similar. In both species, the majority of supraoptic neurons contained vasopressin, however the proportion of vasopressin-containing neurons in the human paraventricular nucleus was double that of the rat (nearly a 100-fold increase in number). These results suggest that the paraventricular nucleus contributes significantly to the release of vasopressin from the posterior pituitary in humans, whereas in rats vasopressin is mainly released by supraoptic neurons.

Animals↗

PubMed1994

Practical considerations for the use of the optical disector in estimating neuronal number.

The aim of this study was to establish methodological variability in the estimation of the total number of neurones using the optical disector. Variations in the 3 dimensions of the disector probe were analysed under uniform sampling conditions in 50-microns-thick frozen sections of the human mediodorsal thalamic nucleus. There was no significant difference between the estimated neuronal number using samples of variable height (fractionator vs. non-fractionator sampling). In addition, different methods of volume calculation (individual sample vs. an average) did not significantly change the estimated total neuronal number. Large variations in the estimated total neuronal number occurred when the x and y dimensions of the disector probe were altered. In this study, accurate and reproducible estimates were achieved when the disector probe was large enough to have a probability of sampling at least 2 cells per frame. We conclude that the variables in the x-y plane (the disector frame size as well as the sample interval) significantly contribute to differences in the estimated total neuronal number. Several practical measurements to estimate this probability and enhance experimental design are discussed.

Cell Count↗

PubMed1992

Cost benefits of low dose subcutaneous erythropoietin in patients with anaemia of end stage renal disease.

OBJECTIVE: To assess the cost benefits of low dose subcutaneous recombinant human erythropoietin in correcting the anaemia of end stage renal disease. DESIGN: Three year retrospective study. SETTING: Subregional nephrology service serving a mixed urban and rural population of 800,000. SUBJECTS: 60 patients with symptoms of anaemic end stage renal disease treated with erythropoietin (43 receiving haemodialysis; 11 receiving continuous ambulatory peritoneal dialysis; two with predialysis end stage renal disease; four with failing renal transplants). MAIN OUTCOME MEASURES: Costs and savings of achieving and maintaining a haemoglobin concentration of 85-105 g/l with erythropoietin. RESULTS: All patients treated with erythropoietin achieved the target haemoglobin concentration at median induction doses of 97 (95% confidence interval 95 to 108) units/kg/week, and this was maintained with 79 (75 to 95) units/kg/week at an average annual cost per patient of 2260 pounds. Admissions related to anaemia were virtually eliminated (246 v 1 inpatient days for 12 months before and after starting erythropoietin). 54 patients required no blood transfusions after starting erythropoietin, and the total requirements fell from 230 to 21 units in the 12 months before and after starting erythropoietin. Iron stores were maintained with oral or intravenous iron. All patients reported increased wellbeing, appetite, and exercise capacity. Hypertension developed or worsened in 30 patients, resulting in hospital admissions in five patients, one of whom had seizures. CONCLUSION: Low dose subcutaneous erythropoietin restores haemoglobin concentrations sufficiently to abolish blood transfusion requirements and reduce morbidity. The net cost of erythropoietin prescribed in this way (2260 pounds/patient/year) was largely offset by savings in costs of hospital admissions. The true annual cost to the NHS was around 1200 pounds per patient.

Adult↗