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S M Gentleman

Publications and source records attributed to S M Gentleman.

At least 19 recordsLinked to original sources
PubMed2005

Amyloid beta peptide causes chronic glial cell activation and neuro-degeneration after intravitreal injection.

We have previously demonstrated that amyloid beta (Abeta) peptide is acutely toxic to retinal neurones in vivo and that this toxicity is mediated by an indirect mechanism. We have now extended these studies to look at the chronic effect of intravitreal injection of Abeta peptides on retinal ganglion cells (RGC), the projection neurones of the retina and the glial cell response. 5 months after injection of Abeta1-42 or Abeta42-1 there was no significant reduction in RGC densities but there was a significant reduction in the retinal surface area after both peptides. Phosphate-buffered saline (PBS) injection had no effect on retinal size or RGC density. There was a pronounced reduction in the number of large RGCs with a concomitant significant increase in medium and small RGCs. There was no change in cell sizes 5 months after injection with PBS. At 5 months after injection of both peptides, there was marked activation of Muller glial cells and microglia. There was also expression of the major histocompatibility complex (MHC) class II molecule on some of the microglial cells but we saw no evidence of T-cell infiltration into the injected retinas. In order to elucidate potential toxic mechanisms, we have looked at levels of glutamine synthetase and nitric oxide synthase. As early as 2 days after injection we noted that activation of Muller glia was associated with a decrease in glutamine synthetase immuno-reactivity but there was no detectable expression of inducible nitric oxide synthase in any retinal cells. These results suggest that chronic activation of glial cells induced by Abeta peptides may result in chronic atrophy of projection neurones in the rat retina.

Amyloid beta-Peptides↗
PubMed2005

Cerebral amyloid angiopathy in traumatic brain injury: association with apolipoprotein E genotype.

OBJECTIVE: In view of the association of the apolipoprotein E (APOE) epsilon 4 allele with poor outcome after traumatic brain injury we determined the frequency of cerebral amyloid angiopathy (CAA) and the extent of haemorrhagic pathology in relation to APOE genotype in an autopsy series of 88 head injured cases. METHODS: Tissue sections from the frontal and temporal lobes were immunostained for amyloid-beta peptide (A beta) and stained for Congo red to identify vascular amyloid pathology. A semiquantitative assessment of contusions, the total contusion index, was used to estimate the severity of the haemorrhagic pathology. APOE genotypes were determined by polymerase chain reaction of genomic DNA extracted from paraffin embedded tissue sections. RESULTS: CAA was present in 7/40 (18%) epsilon 4 carriers compared with 1/48 (2%) non-epsilon 4 carriers (p = 0.021, 95% confidence interval (CI) for difference in proportions with CAA 3% to 29%) with 6/40 (4 with CAA) epsilon 4 carriers being homozygotes. Thus the risk of having CAA for epsilon 4 carriers was 8.4 times that for the non-epsilon 4 carriers. However, there was no clear tendency for patients with CAA to have more severe or more numerous contusions (median contusion index 19 (CAA) v 14.5, p = 0.23, 95% CI for difference in medians -5 to 14). CONCLUSIONS: Presence of CAA in head injured cases was significantly associated with possession of an APOE epsilon 4 allele but not with the severity of contusions.

Adolescent↗
PubMed2004

Long-term intracerebral inflammatory response after traumatic brain injury.

Epidemiological and pathological studies suggest that head injury is a significant risk factor for subsequent neurodegeneration and cognitive decline in later life. The precise mechanisms for the development of post-traumatic neurodegenerative change are unclear but we hypothesize that persistence of inflammatory processes in the brain may play a key role and that some individuals are more susceptible to such changes based on their genetic make-up. In support of this hypothesis we present evidence of persistent elevated microglial activity in long-term survivors of head injury and the suggestion of an association between the extent of this activity and interleukin-1 genotype.

Adolescent↗
PubMed2004

Trials and tribulations of using beta-amyloid precursor protein immunohistochemistry to evaluate traumatic brain injury in adults.

Axonal pathology is increasingly identified by beta-amyloid precursor protein (betaAPP) immunohistochemistry in the brains of patients who may or may not have a history of trauma. The presence of betaAPP-IR(+) has been variously interpreted as either that diffuse traumatic axonal injury (TAI) is indeed a universal finding in cases of fatal traumatic brain injury (TBI) or there are other causes of betaAPP-IR(+) axons which under certain circumstances may be sufficient to mimic TBI and therefore make the medico-legal interpretation of certain cases very difficult. To address some of the uncertainties we have undertaken a detailed analysis of the amount and distribution of betaAPP immunohistochemistry in 63 cases of fatal TBI, 17 cases of patients dying after cardiac arrest, 12 cases dying in association with status epilepticus, 3 cases of carbon monoxide (CO) poisoning, 13 cases of hypoglycaemia and in 60 controls. Three patterns of betaAPP-IR(+) were identified. First, diffuse multi-focal, second, corresponding to the outline of an infarct or haematoma, and thirdly a mixture of the two. The first pattern was seen in cases of the lesser grades of TAI, CO poisoning, and hypoglycaemia, the second pattern in cases in which there was evidence of raised intracranial pressure and the third in cases of severe TAI. It is concluded that the proper interpretation of cases requires the examination of a sufficient number of blocks ( [Formula: see text] ), processing using standardised protocols including betaAPP immunohistochemistry and in some cases the mapping of any IR(+) on anatomical line diagrams. betaAPP carried out on a small number of randomly taken blocks is likely to lead to misinterpretation of the clinico-pathological correlations and possibly to a miscarriage of justice.

Adolescent↗
PubMed2001

Axonal injury is accentuated in the caudal corpus callosum of head-injured patients.

Amyloid precursor protein (APP) accumulation is a sensitive marker for the axonal damage that is commonly seen in the brain as the result of head injury. This form of damage is particularly associated with midline structures such as the corpus callosum, although it is not clear whether some areas are more susceptible than others. The aim of this study was to determine if there was a differential distribution of axonal injury throughout the corpus callosum after head injury in an unselected group of cases. Coronal tissue sections from eight cases were taken at different levels through the corpus callosum, including the genu, body, and splenium. The sections were immunostained with an antibody to APP, and the amount of axonal damage at the different levels was quantified using computer image analysis to build up a rostro-caudal profile for each case. The profiles revealed a significantly higher APP load in caudal parts of the corpus callosum. This supports previous nonquantitative reports in the literature and has important implications in terms of choosing where tissue should be sampled to maximize the chance of detecting axonal injury post mortem.

Adolescent↗
PubMed2000

beta-amyloid (Abeta)42(43), abeta42, abeta40 and apoE immunostaining of plaques in fatal head injury.

beta-Amyloid (Abeta) deposits are found in the brains of approximately one-third of patients who die within days after a severe head injury; their presence correlating strongly with possession of an apolipoprotein E (apoE)-epsilon4 allele. The aim of the study was to investigate the relationship between Abeta42, Abeta40 and apoE immunostaining of Abeta plaques in the cerebral cortex and the relevance of apoE genotype in 23 fatally head-injured patients. These cases were known to have Abeta deposits from a previous study in which they were examined and semiquantified and related to apoE genotype. In the present study, the temporal cortex was probed using four different antibodies that recognize Abeta42(43), Abeta40 and an antibody to apoE. Abeta42(43)-positive plaques were observed in all of the 23 cases and Abeta40 immunoreactivity in only 11 of the 23 cases. In addition, semiquantitative analysis showed that relatively fewer plaques were detected with anti-Abeta40 than anti-Abeta42(43). ApoE-immunoreactive plaques were identified in 18 of the 23 cases. The number of plaques stained for apoE was relatively less than for Abeta42(43) but greater than for Abeta40. Furthermore, the density of Abeta plaques detected using either Abeta42(43), Abeta40 or apoE antibodies was associated with possession of apoE-epsilon4 in an allele dose-dependent manner. The results are consistent with Abeta42(43) as the initially deposited species in brain parenchyma and provide evidence that apoE is involved in the early stages of amyloid deposition. Further, the findings may be of relevance to the role of apoE genotype in influencing outcome after acute brain injury.

Adolescent↗
PubMed2000

Increase in HLA-DR immunoreactive microglia in frontal and temporal cortex of chronic schizophrenics.

Glia play a major role in neuronal migration, synapse formation, and control of neurotransmission in the developing and mature nervous system. This study investigated whether chronic schizophrenia is associated with glial changes in 3 regions of the cerebral cortex: dorsolateral prefrontal cortex (Brodmann's area 9), the superior temporal gyrus (area 22), and the anterior cingulate gyrus (area 24). In a blind study, astroglia and microglia were identified immunocytochemically in frozen sections from postmortem schizophrenic and control brains. Astroglia and microglia were identified using antibodies to glial fibrillary acidic protein (GFAP) and class II human leucocyte antigen (HLA-DR) respectively. They were then quantified for each cortical layer. Significant differences were found in HLA-DR+ microglial numerical density in 2 of the areas. A 28% increase (p < 0.05) was found in area 9 in 8 schizophrenics (115 +/- 9 cells/mm2) compared with 10 controls (89 +/- 5 cells/mm2), when combining all cortical layers and both cerebral hemispheres. For area 22, there was a 57% increase (p < 0.01) in microglia in 7 schizophrenics (139 +/- 6 cells/mm2) compared with 10 controls (88 +/- 5 cells/mm2). In area 24 the same trend was evident, but the results did not reach significance. Microglial number was further analyzed for each cortical layer, which confirmed the overall pattern. For all areas, numerical density of astroglia showed no significant differences between schizophrenics and controls. Cortical thickness was measured in all areas and total neuronal numerical density was estimated for area 22. Again, no significant differences were found between schizophrenics and controls. This study demonstrates a specific increase in the numerical density of HLA-DR+ microglia in temporal and frontal cortex of chronic schizophrenics, not related to aging, which might be implicated in possible changes in cortical neuropil architecture in schizophrenia.

Age Factors↗
PubMed1999

Effects of bFGF and TGFbeta on the expression of amyloid precursor and B-cell lymphoma protooncogene proteins in the rat retina.

The pattern of immunoreactivity for amyloid precursor (APP) and B-cell lymphoma protooncogene (Bcl-2) proteins in the rat retina was studied after intravitreal injection of basic fibroblast growth factor (bFGF) or transforming growth factor-beta (TGFbeta). In normal control retinas, intense immunostaining of APP and Bcl-2 was observed primarily in the endfeet and proximal part of radial processes of Müller glial cells. A dose-dependent reduction in immunostaining of APP and Bcl-2 in Müller cells was observed after injection of bFGF and TGFbeta. These results provide the first evidence that APP and Bcl-2 can be down-regulated by cytokines in vivo.

Amyloid beta-Protein Precursor↗
PubMed1999

Is there a genetic basis for the deposition of beta-amyloid after fatal head injury?

1. Alzheimer's disease is a heterogeneous disorder that may be caused by genetic or environmental factors or by a combination of both. Abnormalities in chromosomes 1, 14, and 21 have all been implicated in the pathogenesis of the early-onset form of the disease, while the epsilon 4 allele of the apolipoprotein E gene (on chromosome 19) is now recognized as a risk factor for early- and late-onset sporadic and familial Alzheimer's disease. 2. The best-established environmental trigger for the disease is a head injury, based on epidemiological and neuropathological evidence. Approximately 30% of patients who die after a single episode of severe head injury show intracerebral deposition of beta-amyloid protein (A beta), a protein that is thought to be central to the pathogenesis of Alzheimer's disease. 3. Recent studies have revealed an over-representation of the apoE epsilon 4 allele in those head-injured patients displaying A beta pathology, thus providing the first evidence for a link between a genetic susceptibility (apoE epsilon 4) and an environmental trigger (head injury) in the development of Alzheimer-type pathology.

Adolescent↗
PubMed1999

A comparison of manual and semi-automated methods in the assessment of axonal injury.

Diffuse axonal injury (DAI) in the central nervous system is a common cause of post-traumatic coma and may result in varying degrees of disability up to and including the vegetative state. Experimental studies in man and animals have previously relied upon semi-quantitative grading systems for determining the relationship between the extent of DAI and the clinical features of patients. Using beta-amyloid precursor protein immunocytochemistry for the detection of DAI in sections of corpus callosum from 15 cases of fatal head injury, we have developed a quantitative image analysis technique for the assessment of axonal injury. This new method is objective and reproducible and should allow better correlation with biomechanical, radiological, and clinical parameters to increase our understanding of DAI.

Adolescent↗
PubMed1999

Overexpression of s100beta in Down's syndrome: correlation with patient age and with beta-amyloid deposition.

S100beta is an astrocyte-derived uritotrophic' cytokine which has been implicated in the pathogenesis of Alzheimer's disease. S100beta overexpression by plaque-associated astrocytes correlates with growth of abnormal (strophic') neurites in beta-amyloid plaques, one of the major neuropathological hallmarks of Alzheimer's disease. As the characteristic neuropathological changes of Alzheimer's disease are virtually universal in middle-aged Down's syndrome patients, studies of Down's syndrome patients provide a unique opportunity to investigate the pathophysiological processes underlying the development of Alzheimer-type neuropathological changes. Computerized morphometric analysis was used to quantify astrocyte activation and astrocytic expression of S100beta, and to correlate these with beta-amyloid deposition, in a clinically well-characterized cohort of Down's syndrome subjects, aged 13-65 years. There were significant positive correlations between S100beta expression and patient age, and between S100beta expression and cerebral cortical beta-amyloid deposition. Moreover, the numbers of activated (enlarged) astrocytes overexpressing S100beta showed a significant correlation with the numeric density of beta-amyloid plaques, from the youngest to the oldest ages and within age ranges where pathology is most florid, while no such relationship was found between the numbers of small, non-activated S100beta-immunoreactive cells and numerical density of beta-amyloid plaques. These correlations, together with established functions of S100beta, are consistent with the idea that S100beta overexpression promotes beta-amyloid plaque formation and progression in Down's syndrome.

Adolescent↗
PubMed1998

Glial-neuronal interactions in Alzheimer's disease: the potential role of a 'cytokine cycle' in disease progression.

The role of glial inflammatory processes in Alzheimer's disease has been highlighted by recent epidemiological work establishing head trauma as an important risk factor, and the use of anti-inflammatory agents as an important ameliorating factor, in this disease. This review advances the hypothesis that chronic activation of glial inflammatory processes, arising from genetic or environmental insults to neurons and accompanied by chronic elaboration of neuroactive glia-derived cytokines and other proteins, sets in motion a cytokine cycle of cellular and molecular events with neurodegenerative consequences. In this cycle, interleukin-1 is a key initiating and coordinating agent. Interleukin-1 promotes neuronal synthesis and processing of the beta-amyloid precursor protein, thus favoring continuing deposition of beta-amyloid, and activates astrocytes and promotes astrocytic synthesis and release of a number of inflammatory and neuroactive molecules. One of these, S100beta, is a neurite growth-promoting cytokine that stresses neurons through its trophic actions and fosters neuronal cell dysfunction and death by raising intraneuronal free calcium concentrations. Neuronal injury arising from these cytokine-induced neuronal insults can activate microglia with further overexpression of interleukin-1, thus producing feedback amplification and self-propagation of this cytokine cycle. Additional feedback amplification is provided through other elements of the cycle. Chronic propagation of this cytokine cycle represents a possible mechanism for progression of neurodegenerative changes culminating in Alzheimer's disease.

Alzheimer Disease↗
PubMed1997

Nitric oxide synthase in developing retinas and after optic tract section.

We compared the pattern of nitric oxide synthase (NOS) immunoreactivity in retinas of rats during normal development and after unilateral transection of the optic tract at postnatal day 7. NOS was first detected in the second postnatal week in the inner nuclear and inner plexiform layers. There was no detectable difference in the overall pattern of immunoreactivity between normal retinas and retinas with severe loss of ganglion cells due to the lesion. We suggest that NOS may have a role in synaptic and vascular development in the inner retina, but is unlikely to play a major role in normal physiological retinal ganglion cell death or axotomy-induced cell death.

Animals↗
PubMed1997

A beta 42 is the predominant form of amyloid beta-protein in the brains of short-term survivors of head injury.

Fatal head injury results in the formation of diffuse parenchymal deposits of amyloid beta-protein (A beta) in the brains of approximately 30% of individuals. We used carboxyl terminal-specific antisera to examine the exact nature of these deposits in paraffin sections of neocortex from seven head-injured patients. Immunostaining for A beta 42 was observed in all parenchymal deposits whereas staining for A beta 40, the form of the protein which predominates in serum and cerebrospinal fluid, was seen in only a small proportion of deposits. The relative paucity of A beta 40 suggests that post-traumatic deposits do not arise as a result of passive leakage from damaged cerebral blood vessels but are similar to the early A beta 42 parenchymal deposits seen in Down's syndrome and Alzheimer's disease.

Adolescent↗
PubMed1997

Prion protein immunocytochemistry--UK five centre consensus report.

Creutzfeldt-Jakob disease (CJD) and other prion diseases are associated with the deposition of insoluble prion protein (PrPCJD) in the central nervous system (CNS). Antibodies raised against PrPCJD also react with its precursor protein, a soluble form of PrP (PrPC), which is widely distributed in the normal CNS. This cross-reactivity has in the past raised doubts as to the specificity and diagnostic reliability of PrP immunolocalization, especially in familial cases which are atypical clinically and which lack characteristic pathology findings. Following an MRC-funded workshop which focused on this problem, a multicentre prospective study was set up to identify a reliable protocol for PrPCJD immunocytochemistry. Five UK centres took part in this study and demonstrated consistent staining of plaques, vacuolar deposits in severe spongiform change, and perineuronal deposits using a variety of antibodies and enhancement procedures. A protocol using formic acid, guanidine thiocyanate, and hydrated autoclaving pre-treatment in conjunction with a monoclonal PrPCJD antibody produced the clearest immunochemical results and is presented as the consensus UK recommendation for PrPCJD immunocytochemical procedures.

Brain↗