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Biomedical subjects

D I Graham

Publications and source records attributed to D I Graham.

At least 73 records · Page 4Linked to original sources
PubMed1999

The apolipoprotein E epsilon2 allele and the pathological features in cerebral amyloid angiopathy-related hemorrhage.

Cerebral amyloid angiopathy (CAA) is associated with apolipoprotein E (APOE gene, apoE protein) polymorphism: current evidence suggests that the epsilon4 allele is a risk factor for the development of CAA and the epsilon2 allele predisposes to hemorrhage. We sought to determine the relationship between the APOE epsilon2 allele and both the immunoreactivity profiles and vascular complications of CAA. We performed immunohistochemistry for amyloid beta-protein (A beta), apoE, cystatin C, and activated microglia, and examined the morphology of cortical and leptomeningeal vessels in 37 CAA-related hemorrhage (CAAH), 26 Alzheimer disease (AD) patients, and 20 controls. The extent of immunostaining of vessels for A beta, apoE, cystatin C, and perivascular activated microglia increased from controls through AD to a maximum in CAAH patients. Among cases with CAA (37 CAAH, 19 AD, and 6 controls, n = 62) vascular apoE (p < 5 x 10(-4)), cystatin C (p < 10(-4)), activated microglia (p < 10(-4)), vessels with a high ratio of wall thickness to lumen diameter (p < 0.003) as well as dilated/microaneurysmal vessels (p < 0.01) were present more frequently in patients with hemorrhage than without; however, these features were not associated with the APOE epsilon2 allele. Fibrinoid necrosis alone was associated with the APOE epsilon2 allele (p < 0.04) and we suggest that over-representation of APOE epsilon2 in CAAH may result from its association with fibrinoid necrosis.

Aged↗
PubMed1998

Protection by an adenosine analogue against kainate-induced extrahippocampal neuropathology.

1. The glutamate analogue kainic acid produces neuronal damage in the central nervous system. We have reported that analogues of adenosine, such as R-N6-phenylisopropyladenosine (R-PIA) can, at doses as low as 10 microg/kg IP, prevent the hippocampal damage that follows the systemic administration of kainate. The present work was designed to examine purine protection against kainate in extrahippocampal regions by using histological methods. 2. The results show that R-PIA, at a dose of 25 microg/kg IP in rats, can protect against the neuronal damage caused by kainate in the basolateral amygdaloid nuclei, the pyriform cortex and around the rhinal fissure. This protection could be prevented by the simultaneous administration of the A1 adenosine receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine, confirming that the protection involved adenosine A1 receptors. No protection was observed in the posterior amygdaloid nuclei or the entorhinal cortex, suggesting the absence of relevant adenosine receptors or a different mechanism of excitotoxicity.

Adenosine↗
PubMed1998

Topographical and quantitative assessment of white matter injury following a focal ischaemic lesion in the rat brain.

Axonal injury following cerebral ischaemia has attracted less attention than damage in grey matter. However, it is becoming increasingly recognised that axons are highly vulnerable to focal ischaemia [D. Dewar, D.A. Dawson, Changes of cytoskeletal protein immunostaining in myelinated fibre tracts after focal cerebral ischaemia in the rat, Acta. Neuropathol., 93 (1997) 71-77] [2]; [L. Pantoni, J.H. Garcia, J.A. Gutierrez, Cerebral white matter is highly vulnerable to ischemia, Stroke, 27 (1996) 1641-1647] [10]; [P. S. Yam, T. Takasago, D. Dewar, D.I. Graham, J. McCulloch, Amyloid precursor protein accumulates in white matter at the margin of a focal ischaemic lesion, Brain Res., 760 (1997) 150-157] [15]. Since white matter does not contain neuronal cell bodies or synapses it is likely that the mechanisms of injury and strategies for its protection are different from those in grey matter. In order that the effect of therapeutic intervention on the protection of axons can be assessed, a method by which axonal injury can be mapped and quantified is required. For this purpose, we investigated immunocytochemical methods using amyloid precursor protein (APP) following permanent middle cerebral artery occlusion in the rat. APP is transported by fast anterograde axonal transport [E.H. Koo, S.S. Sisodia, D.R. Archer, L.J. Martin, A. Weidemann, K. Beyreuther, P. Fischer, C.L. Masters, D.L. Price, Precursor of amyloid protein in Alzheimer disease undergoes fast anterograde axonal transport, Proc. Natl. Acad. Sci. U.S.A. 87 (1990) 1561-1565] [7] and has been shown to accumulate following a variety of insults to axons, indicative of dysfunction of axonal transport [R.N. Kalaria, S.U. Bhatti, E.A. Palatinsky, D.H. Pennington, E.R. Shelton, H.W. Chan, G. Perry, W.D. Lust, Accumulation of the beta amyloid precursor protein at sites of ischemic injury in rat brain, Neuroreport, 4 (1993) 211-214] [4]; [T. Kawarabayashi, M. Shoji, Y. Harigaya, H. Yamaguchi, S. Hirai, Expression of APP in the early stage of brain damage, Brain Res., 563 (1991) 334-338] [5]; [N. Otsuka, M. Tomonaga, K. Ikeda, Rapid appearance of beta-amyloid precursor protein immunoreactivity in damaged axons and reactive glial cells in rat brain following needle stab injury, Brain Res., 568 (1991) 335-338] [9]; [K. Shigematsu, P. L. McGeer, Accumulation of amyloid precursor protein in neurons after intraventricular injection of colchicine, Am. J. Pathol., 140 (1992) 787-794] [12]. We have been able to map the topographical relationship between APP accumulation and region of infarction using immunocytochemistry and image analysis techniques. Additionally, using a semi-quantitative scoring system, we have demonstrated that there is a relationship between the amount of APP accumulation and the volume of infarction following middle cerebral artery occlusion. These methods will be useful in the future for the assessment of therapeutic interventions on the protection of axons following ischaemic injury.

Amyloid beta-Protein Precursor↗
PubMed1998

Selective astrocytic transgene expression in vitro and in vivo from the GFAP promoter in a HSV RL1 null mutant vector--potential glioblastoma targeting.

Due to the lack of any effective therapy, novel approaches are currently being explored for the treatment of primary brain tumours. It has previously been demonstrated that variants of HSV-1 which are deleted in the RL1 gene and fail to produce the virulence factor ICP34.5 are potential candidates for tumour therapy. The RL1 variant 1716 replicates selectively within tumour cells and has the potential to deliver a therapeutic or tumour killing gene directly to the site of tumour growth. As many intracerebral tumours are glial and predominantly astrocytic in origin, we have evaluated the ability of 1716 to deliver a reporter gene specifically to astrocytes in vivo and in vitro using a 2.2 kb fragment which controls expression of the glial fibrillary acidic protein (GFAP), an astrocyte specific protein. Two 1716 variants, 1774 and 1775, were constructed which contain the GFAP-promoter element linked to the E. coli beta-galactosidase gene, inserted into the HSV-1 UL43 and US5 loci, respectively. In primary cultures, human primary tumour cell lines and established tumour cell lines in vitro, 1774 and 1775 gave high levels of expression of beta-galactosidase specifically in astrocytes. In vivo following intracerebral inoculation, both viruses demonstrated high levels of beta-galactosidase expression predominantly in astrocytes. These results indicate that the GFAP promoter element could be used for efficient and selective transgene delivery to human gliomas.

Animals↗
PubMed1998

The Dorothy Russell Memorial Lecture. The molecular and cellular sequelae of experimental traumatic brain injury: pathogenetic mechanisms.

The mechanisms underlying secondary or delayed cell death following traumatic brain injury (TBI) are poorly understood. Recent evidence from experimental models of TBI suggest that diffuse and widespread neuronal damage and loss is progressive and prolonged for months to years after the initial insult in selectively vulnerable regions of the cortex, hippocampus, thalamus, striatum, and subcortical nuclei. The development of new neuropathological and molecular techniques has generated new insights into the cellular and molecular sequelae of brain trauma. This paper will review the literature suggesting that alterations in intracellular calcium with resulting changes in gene expression, activation of reactive oxygen species (ROS), activation of intracellular proteases (calpains), expression of neurotrophic factors, and activation of cell death genes (apoptosis) may play a role in mediating delayed cell death after trauma. Recent data suggesting that TBI should be considered as both an inflammatory and/or a neurodegenerative disease is also presented. Further research concerning the complex molecular and neuropathological cascades following brain trauma should be conducted, as novel therapeutic strategies continue to be developed.

Animals↗
PubMed1998

Histopathological responses in the CNS following inoculation with a non-neurovirulent mutant (1716) of herpes simplex virus type 1 (HSV 1): relevance for gene and cancer therapy.

The RL1 gene of herpes simplex virus (HSV) encodes a polypeptide, ICP34.5 which is a specific virulence determinant. RL1 null mutants fail to replicate in both the PNS and CNS and are incapable of causing encephalitis. Additionally, RL1 null mutants have the capacity to replicate in actively dividing cells but fail to replicate in growth arrested or terminally differentiated cells. This selective replication phenotype has highlighted their use as both tumour killing agents and gene delivery vehicles particularly to the nervous system. Before their full potential can be assessed, however, it is necessary to determine the pathological and immune responses induced following direct intracerebral inoculation. Fourteen mice were injected in the left cerebral hemisphere with a high dose of the HSV-1, RL1 null mutant 1716. At regular time intervals up to 28 days, the mice were killed and the distribution of virus antigen, histopathological changes and immune responses in the CNS determined by H & E staining and immunohistochemistry. Control mice were injected with either wild type HSV-1 or buffer. At early times post-inoculation with 1716, there is a low grade meningoencephalitis with a limited inflammatory response. This is accompanied by virus antigen expression confined to the site of inoculation. By 28 days the CNS is histopathologically normal; virus antigen and immune responses are no longer detectable. These findings demonstrate that infection of the CNS by RL1 null mutants of HSV results in a finite, self-limiting response and highlights their potential for therapeutic use.

Animals↗
PubMed1998

The neuronal cytoskeleton in acute brain injury.

The microtubules, neurofilaments and microfilaments of the neuronal cytoskeleton are essential for the normal functioning of the neurone. Recent studies have shown that disruption of the cytoskeleton may represent a final pathway in many types of neuronal cell injury with both the somato-dendritic and axonal cytoskeleton being affected. This review discusses the current evidence on the role of the neuronal cytoskeleton in the pathogenesis of traumatic brain damage.

Brain Injuries↗
PubMed1998

The neuronal cytoskeleton is at risk after mild and moderate brain injury.

Recent studies have described alterations in cytoskeletal proteins such as microtubule-associated protein 2 (MAP-2) and neurofilament (NF) resulting from moderate and severe experimental brain injury; however, few have investigated the consequences of mild injury, which is associated clinically and experimentally with cognitive dysfunction and neuronal damage. To contrast cytoskeletal changes within 7 days following mild injury with those following moderate injury, we subjected anesthetized, adult rats to mild (1.1-1.3 atm) or moderate (2.3-2.5 atm) lateral fluid percussion brain injury or sham injury. Rats were sacrificed at 6 h (n=4 mild; n=4 moderate; n=2 sham), 24 h (n=4 mild; n=4 moderate; n=1 sham), or 7 days (n=5 mild; n=4 moderate; n=1 sham) following injury, and immunohistochemistry was performed for MAP-2 and NF. Both mild and moderate injury produced notable cytoskeletal changes in multiple brain regions; however, mild injury generally resulted in a lesser degree of MAP-2 and NF loss over a smaller spatial extent. When compared to moderately injured animals, animals subjected to mild injury showed substantially delayed MAP-2 and NF alterations within the cortex and hippocampal dentate gyrus and no evidence of MAP-2 loss in the hippocampal CA3 region. While mild and moderate injury resulted for the most part in similar patterns of axonal injury, tissue tears in the fimbria and loss of NF immunoreactivity in regions containing injured axons were only observed following moderate injury. Elucidating the effects of modulating injury severity may yield insight into the mechanisms involved in traumatic damage to the cytoskeleton and guide future treatment strategies.

Animals↗
PubMed1998

Cortical cholinergic dysfunction after human head injury.

Loss of cholinergic neurotransmission is implicated in memory impairment and cognitive dysfunction after head injury. The aim of the present study was to investigate presynaptic markers, particularly in relation to cholinergic neurotransmission in human postmortem brain from patients who died following a head injury and age-matched controls. Choline acetyltransferase activity and high-affinity nicotinic receptor binding sites were assayed in the inferior temporal gyrus, cingulate gyrus, and superior parietal cortex of 16 head-injured patients and 8 controls. Synaptophysin immunoreactivity was determined in the left cingulate gyrus from the same patient groups. In the head-injured group, choline acetyltransferase activity was consistently reduced in each cortical region compared to control subjects. The presence of a subdural haematoma and a prolonged survival period after head injury tended to be associated with lower choline acetyltransferase activity. In contrast to the marked reduction in choline acetyltransferase activity, nicotine receptor binding was unchanged in head-injured compared to control patients. Synaptophysin immunoreactivity in the cingulate gyrus was reduced by approximately 30% (p < 0.05) in the head-injured group compared to controls. Correlation of choline acetyltransferase activity with synaptophysin immunoreactivity indicated there is a deficit of cholinergic presynaptic terminals in postmortem human brain following head injury.

Adult↗
PubMed1998

Axonal cytoskeletal changes after nondisruptive axonal injury. II. Intermediate sized axons.

Earlier studies of axonal cytoskeletal responses to stretch injury in the guinea pig optic nerve, a model of nondisruptive axonal injury such as occurs in human diffuse axonal injury, have demonstrated different cytoskeletal responses between the smallest and largest axons. But these form only approximately 3% of the total number of axons in the optic nerve. It was then posited that the pathology described in the latter axons may not be representative of the pathology in the majority of axons after stretch injury. In order to test this hypothesis, we carried out a quantitative, morphological analysis of structural changes in the cytoskeleton of intermediate (axonal diameter of 0.5-2.0 mM) sized axons at 4 h after stretch injury. Neurofilaments in axons up to 1.00 microm in diameter increased in number and in axons up to 1.50 microm diameter were compacted. This did not occur in larger axons (diameter of 1.51-2.00 microm) in the present study. However, there was focal compaction of neurofilaments in some of the larger fibers at sites where the integrity of the axolemma was lost. The response by microtubules to stretch injury differed from that of neurofilaments in that there was an increased spacing between microtubules and a loss of their number in axons of >1.51 microm diameter. We provide quantitative, morphological evidence (a) that the neurofilamentous cytoskeleton of different sized axons responds in different ways to stretch and (b) that the response by microtubules differs from that of neurofilaments.

Animals↗
PubMed1998

Craniocerebral trauma: protection and retrieval of the neuronal population after injury.

OBJECTIVE: To review the consequences of mechanical injury to the brain with an emphasis on factors that may explain the variability of outcomes and how this might be influenced. METHODS: Information regarding the pathophysiology of traumatic brain damage contained in original scientific reports and in review articles published in recent years was reviewed from the perspective of a clinical neurosurgeon and a neuropathologist, each with major research interests in traumatic brain damage. The information was compiled on the basis of the knowledge of and personal selection of articles that were identified through selective literature searches and current awareness profiles. A systematic literature review was not conducted. RESULTS: Mechanical input affects neuronal and vascular elements and is translated into biological effects on the brain through a complex series of interacting cellular and molecular events. Whether these lead to permanent structural damage or to resolution and recovery is determined by the balance between processes that, on the one hand, mediate the effects of initial injury and subsequent secondary insults and, on the other, are manifestations of the brain's protective, reparative response. Experimental and clinical research has identified opportunities for altering the balance in a way that might promote recovery, but data demonstrating that this can lead to substantial clinical benefit are lacking. Recent evidence of genetically determined, individual susceptibility to the effects of injury may explain some of the puzzling variability in outcome after apparently similar insults and may also provide new opportunities for treatment. CONCLUSION: The understanding of traumatic brain damage that is being gained from recent research is widening and broadening perspectives from the traditional focus on mechanical, vascular, and metabolic effects to encompass wider, neurobiological issues, drawn from the fields of neurodevelopment, neuroplasticity, neurodegeneration, and neurogenetics. Neurotrauma is a fascinating area of neuroscience research, with promise for the translation of knowledge to improved clinical management and outcome.

Animals↗
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

Amyloid precursor protein accumulates in white matter at the margin of a focal ischaemic lesion.

Amyloid precursor protein (APP) is transported by fast anterograde axonal transport. Since disruption of this transport results in APP accumulation, APP has been proposed as a sensitive marker of axonal injury. In the present study, axonal injury in subcortical white matter and myelinated fibre tracts permeating the striatum, 24 h after permanent middle cerebral artery occlusion in the rat, has been examined by assessing the location and extent of APP immunoreactivity. Increased APP immunoreactivity was present in both areas. This was localised to a circumscribed zone immediately adjacent to the boundary of the ischaemic lesion in grey matter. The amount of APP immunoreactivity was associated with the volume of the ischaemic lesion in individual animals. Increased APP immunoreactivity in subcortical white matter and myelinated fibre tracts at the margin of the ischaemic zone may prove to be a valuable marker for assessing strategies to protect axons after an ischaemic insult.

Amyloid beta-Protein Precursor↗
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

High frequency of apolipoprotein E epsilon 2 allele in hemorrhage due to cerebral amyloid angiopathy.

From the somewhat conflicting published data on apolipoprotein E (apoE) genotype in hemorrhage due to cerebral amyloid angiopathy (CAA), it is unclear whether apoE genotype influences the risk of CAA-related hemorrhage independently of its association with concomitant Alzheimer's disease (AD). We determined the apoE genotypes of 36 patients presenting with cerebral hemorrhage associated with histologically confirmed CAA. The frequency of apoE epsilon 2 was 0.25 and the frequency of apoE epsilon 4 was 0.18. Patients with CAA-related hemorrhage and concomitant AD pathology (CERAD criteria, n = 17) had a high apoE epsilon 4 frequency, close to that in AD cases without hemorrhage. Patients in whom CAA-related hemorrhage occurred in the absence of significant AD pathology (n = 13) had an apoE epsilon 4 frequency somewhat lower than non-AD controls without hemorrhage. However, in CAA-related hemorrhage, the apoE epsilon 2 frequency was high regardless of whether significant AD pathology was present. We conclude that whereas possession of apoE epsilon 2 may be a risk factor for cerebral hemorrhage due to CAA, apoE epsilon 4 is a risk factor for concomitant AD but not an independent risk factor for CAA-related hemorrhage.

Aged↗