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Biomedical subjects

I Everall

Publications and source records attributed to I Everall.

At least 19 recordsLinked to original sources
PubMed2004

Cortical selective vulnerability in motor neuron disease: a morphometric study.

Neuroimaging and neuropsychological studies have revealed that the primary motor cortex (PMC) and the extramotor cortical areas are functionally abnormal in motor neuron disease (MND, amyotrophic lateral sclerosis), but the nature of the cortical lesions that underlie these changes is poorly understood. In particular, there have been few attempts to quantify neuronal loss in the PMC and in other cortical areas in MND. We used SMI-32, an antibody against an epitope on non-phosphorylated neurofilament heavy chain, to analyse the size and density of SMI-32-positive cortical pyramidal neurons in layer V of the PMC, the dorsolateral prefrontal cortex (DLPFC) and the supragenual anterior cingulate cortex (ACC) in 13 MND and eight control subjects. There was a statistically significant reduction in the density of SMI-32-immunoreactive (IR) pyramidal neurons within cortical layer V in the PMC, the DLPFC and the ACC in MND subjects compared with controls [t (19) = 2.91, P = 0.009; estimated reduction 25%; 95% CI = 8%, 40%]. In addition, we studied the density and size of interneurons immunoreactive for the calcium-binding proteins calbindin-D(28K) (CB), parvalbumin (PV) and calretinin (CR) in the same areas (PMC, DLPFC and ACC). Statistically significant differences in the densities of CB-IR neurons were observed within cortical layers V (P = 0.003) and VI (P = 0.001) in MND cases compared with controls. The densities of CR- and PV-IR neurons were not significantly different between MND and control cases, although there were trends towards reductions of CR-IR neuronal density within the same layers and of PV-IR neuronal density within cortical layer VI. Loss of pyramidal neurons and of GABAergic interneurons is more widespread than has been appreciated and is present in areas associated with neuroimaging and cognitive abnormalities in MND. These findings support the notion that MND should be considered a multisystem disorder.

Aged↗
PubMed2004

Guidelines for the diagnosis and management of neurological complications of HIV infection.

The spectrum of neurological complications of HIV-infection has remained unchanged through the years, but its epidemiology changed remarkably as a result of the introduction of highly active antiretroviral therapy (HAART). Guidelines for the diagnosis and treatment of cerebral toxoplasmosis, cryptococcal meningitis, progressive multifocal leukoencephalopathy, CMV encephalitis, CMV polyradiculomyelitis, tuberculous meningitis, primary CNS lymphoma, HIV dementia, HIV myelopathy and HIV polyneuropathy are given with a grading of evidence and recommendations.

Anti-HIV Agents↗
PubMed2002

Ubiquitin-only intraneuronal inclusion in the substantia nigra is a characteristic feature of motor neurone disease with dementia.

Two types of ubiquitinated inclusions have been described in motor neurone disease (MND). (1) Skein or globular ubiquitinated inclusions in the motor neurones (more frequently in the lower motor neurones). This is a characteristic feature of all motor neurone disease categories. (2) Dot-shape or crescentric ubiquitinated inclusions in the upper layers of cortex and dentate gyrus described in cases of motor neurone disease with dementia (DMND). We investigated the substantia nigra (SN) in MND cases; two cases of motor neurone disease inclusion body (MND-IB) dementia, six cases of DMND, 14 cases of MND (including one case from Guam and two cases of familial SOD1 mutation), four cases of Parkinson's disease (PD), and 10 cases of age-matched normal controls. SN and spinal cord sections were stained with ubiquitin (alpha-synuclein, tau, PGM1, SMI-31 and SOD1 antibodies). The neuronal density in SN was quantified by using a computer-based image analysis system. Four out of six DMND cases showed rounded ubiquitin positive inclusions with irregular frayed edges, associated with neuronal loss, reactive astrocytosis and a large number of activated microglia cells. These inclusions are negative with antibodies to (alpha-synuclein, tau, SMI-31 and SOD1). The SN in cases from MND-IB dementia and MND showed occasional neuronal loss and no inclusions. The ubiquitin-only inclusions in SN of DMND cases are similar (but not identical) to the ubiquitinated inclusions described previously in the spinal cord of MND cases and are distinct from Lewy bodies (LBs). The degeneration of SN is most likely a primary neurodegenerative process of motor neurone disease type frequently involving the DMND cases. MND disease is a spectrum and multisystem disorder with DMND located at the extreme end of a spectrum affecting the CNS more widely than just the motor system.

Aged↗
PubMed2001

Glycogen synthase kinase-3beta immunoreactivity is reduced in the prefrontal cortex in schizophrenia.

Cytoarchitectural abnormalities have been reported in the cortex in schizophrenia. These suggest a developmental origin for this disorder. The Wnt signalling pathway is involved in the regulation of brain development; disruption of this pathway may lead to abnormal cortical development. In this study levels of three components of the Wnt signalling pathway; glycogen synthase kinase-3beta(GSK-3beta), beta-catenin and dishevelled-2 (Dvl-2) were determined in the prefrontal cortex of ten schizophrenic and ten control individuals using immunoblotting. GSK-3beta levels were significantly reduced in the schizophrenic group, while levels of beta-catenin and Dvl-2 did not differ between groups. This provides further evidence for an abnormality of the Wnt signalling pathway in schizophrenia.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Reduced glial cell density and neuronal size in the anterior cingulate cortex in major depressive disorder.

BACKGROUND: Glial cells are more numerous than neurons in the cortex and are crucial to neuronal function. There is evidence for reduced neuronal size in schizophrenia, with suggestive evidence for reduced glial cell density in mood disorders. In this investigation, we have simultaneously assessed glial cell density and neuronal density and size in the anterior cingulate cortex in schizophrenia, major depressive disorder, and bipolar disorder. METHODS: We examined tissue from area 24b of the supracallosal anterior cingulate cortex in 60 postmortem brain specimens from 4 groups of 15 subjects, as follows: major depressive disorder, schizophrenia, bipolar disorder, and normal controls. Glial cell density and neuronal size and density were examined in all subjects using the nucleator and the optical disector. RESULTS: Glial cell density (22%) (P =.004) and neuronal size (23%) (P =.01) were reduced in layer 6 in major depressive disorder compared with controls. There was some evidence for reduced glial density in layer 6 (20%) (P =.02) in schizophrenia compared with controls, before adjusting for multiple layerwise comparisons, but there were no significant changes in neuronal size. There was no evidence for differences in glial density or neuronal size in bipolar disorder compared with controls. Neuronal density was similar in all groups to that found in controls. CONCLUSION: These findings suggest that there is reduced frontal cortical glial cell density and neuronal size in major depressive disorder.

Adult↗
PubMed2000

Detection of the human immunodeficiency virus regulatory protein tat in CNS tissues.

Neuropathologically, human immunodeficiency virus (HIV) is associated with a range of inflammatory disorders, extensive cortical neuronal loss, and dendritic and synaptic damage. Although the mechanisms resulting in these abnormalities are still unclear, the neurotoxic effects are thought to be due in part to viral products including the tat gene product. We have previously shown that Tat when presented to neurons extracellularly interacts with neuronal cell membranes to cause neuronal excitation and toxicity in fmole amounts. To determine the role of Tat in mediating HIV encephalitis (HIVE), we detected tat mRNA and protein in tissue extracts of nine patients with HIVE and seven patients without HIVE. Despite long autopsy times and significant degradation, tat mRNA was detected in 4/9 patients with HIVE but not in any of the seven patients without dementia. Similarly, the env mRNA was also detected in 5/9 patients with HIVE but not in the patients without HIVE. However, vif mRNA was detected in both groups of patients with (5/9) or without (2/7) HIVE. Using protein extracts from the brains of the same groups of patients we were unable to detect Tat by enzyme linked immunosorbant assay (ELISA) (sensitivity of 2 ng Tat/ml of brain tissue). However, Tat could be detected immunohistochemically and in protein extracts from the brains of rhesus macaques with encephalitis due to a chimeric strain of HIV and simian immunodeficiency virus (SHIV). Our observations support the role of Tat in the neuropathogenesis of HIV and SHIV encephalitis.

AIDS Dementia Complex↗
PubMed1999

Disturbance of Notch-1 and Wnt signalling proteins in neuroglial balloon cells and abnormal large neurons in focal cortical dysplasia in human cortex.

Determination of neuroglial cell fate and neural tube development during embryogenesis is influenced by the Notch/Wnt signalling pathway. We have studied the localisation of several proteins in the Wnt pathway in focal cortical dysplasia (FCD). This disorder, thought to be due to abnormalities of neuronal migration and differentiation, contains regions of morphologically normal neocortex interrupted by areas of neuronal laminar disorganisation, heterotopic white matter neurons, abnormal large neurons and balloon cells of uncertain histogenesis. We found that the subcellular distribution of several proteins involved in the Wnt pathway differed in regions of FCD from normal cortex, and that within the areas of FCD, the pattern varied with cellular phenotype. Thus, in balloon cells, elevated cytoplasmic levels of dishevelled (Dvl-1) protein were accompanied by an absence of Notch-1, increased adenomatous poliposis coli (APC), altered cytoplasmic beta-catenin, and reduced nuclear expression of beta-catenin. A contrasting pattern of expression was found in abnormal large neurons, which demonstrated elevated levels of Notch-1, and glycogen synthase kinase-3beta (GSK-3beta), and normal levels of APC. Our results are consistent with the notion that Wnt/Notch signalling influences neuroglial cell fate, and suggest that a perturbation of Wnt/Notch signalling may contribute to the neuropathology of FCD.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Glial cell changes in the white matter in temporal lobe epilepsy.

Temporal lobe gliosis and neuronal loss are pathological hallmarks of complex partial seizures. However, the specificity of glial cell changes is not clear. To assess this we studied surgically resected temporal lobes containing either medial temporal sclerosis (MTS) or temporal lobe epilepsy with tumour (TLET) and compared them with idiopathic epilepsy cases and normal controls. We quantitatively assessed glial cell density and mean nuclear volume in the white matter of various temporal gyri and the deep white matter. There was an increase in mean glial cell nuclear volume in MTS and TLET cases in the white matter of superior temporal gyrus, parahippocampal gyrus and deep white matter but not in the white matter of the middle temporal gyrus. In contrast, the densities of glial cells immunopositive for glial fibrillary acidic protein in the MTS and TLET groups were reduced in all white matter regions when compared with the controls. These changes may indicate that glial cells in the white matter have an active role to play in epilepsy pathogenesis.

Adolescent↗
PubMed1999

Focal cortical dysplasia: a neuropathological and developmental perspective.

Focal cortical dysplasia (FCD) is a rare, sporadic disorder which is a recognised cause of chronic epilepsy. It is proposed to result from disordered neuronal migration and differentiation and has characteristic histological features which include disturbed cortical lamination, large abnormal neurons and the presence of large balloon cells with glassy eosinophilic cytoplasm and pleomorphic eccentric nuclei. These latter express both glial and neuronal markers indicative of abnormal neuroglial differentiation. In this paper we review the current literature on the neuropathology of FCD and discuss potential mechanisms. We focus on growth factors, signalling pathways and candidate genes with known roles in Drosophila and vertebrate brain development that could be responsible for the developmental brain changes seen in FCD. At issue are the factors that influence cell fate and differentiation and which regulate neural migration. Some of the molecular pathways, such as those involving the Notch and the Wnt pathways have particularly important roles in neuroglial differentiation in vertebrates, and these are proposed as potential candidates.

Animals↗
PubMed1998

Abnormalities of Wnt signalling in schizophrenia--evidence for neurodevelopmental abnormality.

The Wnt signalling pathway is central to normal brain development in vertebrates and invertebrates and mediates cell fate determination, cell adhesion and cell proliferation. However, its relevance to disorders of cerebral development in man is untested. We evaluated the potential involvement of the Wnt signalling pathway in schizophrenia, a disorder of neurodevelopment origin in which alterations in neuronal lamination and orientation have been described. Using immunohistochemistry and semi-quantitative rating scales, we examined the distribution of two components of the Wnt signalling pathway, beta-catenin and gamma-catenin in the hippocampus and subiculum of 12 schizophrenic (DSMIIR criteria) and 14 control subjects. Both catenins were distributed as intraneuronal diffuse and/or ring shaped forms. The diffuse staining of both forms catenin were reduced in the CA3 and beta-catenin was also reduced in the CA4 hippocampal subregion among schizophrenic subjects. These alternations may represent the basis of the developmental brain abnormalities found in schizophrenia and would have functionally important consequences in the adult.

Adult↗
PubMed1996

Neuropathology of early HIV-1 infection.

Early HIV-1 invasion of the central nervous system has been demonstrated by many cerebrospinal fluid studies; however, most HIV-1 carriers remain neurologically unimpaired during the so called "asymptomatic" period lasting from seroconversion to symptomatic AIDS. Therefore, neuropathological studies in the early pre-AIDS stages are very few, and the natural history of central nervous system changes in HIV-1 infection remains poorly understood. Examination of brains of asymptomatic HIV-1 positive individuals who died accidentally and of rare cases with acute fatal encephalopathy revealing HIV infection, and comparison with experimental simian immunodeficiency virus and feline immunodeficiency virus infections suggest that, invasion of the CNS by HIV-1 occurs at the time of primary infection and induces an immunological process in the central nervous system. This includes an inflammatory T-cell reaction with vasculitis and leptomeningitis, and immune activation of brain parenchyma with increased number of microglial cells, upregulation of major histocompatibility complex class II antigens and local production of cytokines. Myelin pallor and gliosis of the white matter are usually found and are likely to be the consequence of opening of the blood brain barrier due to vasculitis; direct damage to oligodendrocytes by cytokines may also interfere. These white matter changes may explain, at least partly, the early cerebral atrophy observed, by magnetic resonance imaging, in asymptomatic HIV-1 carriers. In contrast, cortical damage seems to be a late event in the course of HIV-1 infection. There is no significant neuronal loss at the early stages of the disease, no accompanying increase in glial fibrillary acid protein staining in the cortex, and only exceptional neuronal apoptosis. Although HIV-1 proviral DNA may be demonstrated in a number of brains, viral replication remains very low during the asymptomatic stage of HIV-1 infection. This makes it likely that, although opening of the blood brain barrier may facilitate viral entry into the brain, specific immune responses including both neutralising antibodies and cytotoxic T-lymphocytes, continuously inhibits viral replication at that stage.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Neuronal pattern correlates with the severity of human immunodeficiency virus-associated dementia complex. Usefulness of spatial pattern analysis in clinicopathological studies.

The spatial distributional pattern of neurons, in the superior frontal gyrus of 32 subjects who died of acquired immune deficiency syndrome, was examined. The patients were classified as nondemented, mildly demented, and severely demented, and some were treated with the anti-retroviral drug zidovudine. Spatial statistical techniques were employed to investigate the degree of clustering in the individual cases and various groups. We found that the cluster pattern of large and small neurons differed significantly with increasing severity of dementia but was not influenced by the duration of zidovudine treatment. We conclude that this is a sensitive technique for clinicopathological correlations and that the differences may result from loss of specific neuronal populations, which could determine the degree of dementia.

AIDS Dementia Complex↗
PubMed1995

Spatial data analysis in the quantitative assessment of cerebral white matter pathology on MRI in HIV infection.

This study was carried out using MRI (proton density--and T2-weighted) on 16 HIV-negative controls, 9 symptom-free HIV-positive patients and 25 with CDC IV HIV disease. The studies from this last group had previously been allocated by a radiologist to the following categories: 8 with focal mass lesions and normal-appearing white matter; 9 with diffuse encephalopathy (high signal on T2-weighted images, affecting most or all of the white matter) and 8 with patchy encephalopathy (high signal affecting only one or two areas within the white matter). Moran's I, a statistic of spatial autocorrelation, was calculated for the grey-scale values of a sampled pixel array from a central white matter region of each of the images. All values of Moran's I calculated in this study showed a large positive excess over the expected value under randomisation, indicating highly significant positive auto-correlation in the spatial arrangement of the grey-scale values. On T2-weighted images a statistically significant increase in the mean value of Moran's I, compared with controls, was found in the diffuse encephalopathy group, indicating that quantifiable changes in the spatial autocorrelation of pixel data can be related to recognised qualitative changes in the appearance of white matter in subjects with HIV disease. A lesser, but significant, rise in the mean value of Moran's I was also found in the focal mass lesion group, suggesting that changes in spatial autocorrelation may indicate pathological change in advance of qualitative MRI changes.

AIDS Dementia Complex↗
PubMed1995

Assessment of neuronal density in the putamen in human immunodeficiency virus (HIV) infection. Application of stereology and spatial analysis of quadrats.

Human immunodeficiency virus causes neuronal loss in various brain regions, but it has not been reported in the putamen. However, decrease in the volume of the putamen has been observed by magnetic resonance imaging. In order to clarify this issue two complementary methods; the stereological probe, the disector, and spatial analysis of quadrats, were applied in nondemented individuals who had died of acquired immune deficiency syndrome. A 21% decrease in neuronal density was observed in the human immunodeficiency virus group, especially those cases with human immunodeficiency virus encephalitis; however the statistical significance of this finding was borderline.

Acquired Immunodeficiency Syndrome↗
PubMed1993

A review of neuronal damage in human immunodeficiency virus infection: its assessment, possible mechanism and relationship to dementia.

Over the past decade it has been realized that HIV affects the central nervous system, and various investigations have illuminated the spectrum of neuropathology in AIDS. One major advance has been the demonstration that there is substantial neuronal loss, which appears independent of the HIV-associated inflammatory lesions. Quantitative studies on neuronal populations, while fraught with methodological difficulties, are essential to the understanding of the mechanism of this neurotoxic damage. This article will review, firstly, the modern stereological procedures available for quantitative investigations; secondly, the pattern, degree and time scale of HIV-associated neuronal loss; thirdly, other morphological evidence of neuronal damage; and finally, the pathological and clinical implications of these findings.

AIDS Dementia Complex↗