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D I Graham

Publications and source records attributed to D I Graham.

At least 163 records · Page 9Linked to original sources
PubMed1991

Selective vulnerability of hippocampal neurons in acceleration-induced experimental head injury.

Traumatically induced subtotal hippocampal neuronal loss traditionally has been considered a consequence of intracranial hypertension and impaired cerebral perfusion. We have examined the frequency and distribution of hippocampal lesions in an acceleration model of brain injury in 54 anesthetized nonhuman primates undergoing physiologic monitoring and subjected postinjury to comprehensive neuropathologic examination. Hippocampal lesions occurred in 32/54 animals (59%). These lesions always involved the CA-1 hippocampal subfield and were bilateral in 24 animals. Hippocampal involvement was not associated with marked elevation of intracranial pressure or depression of cerebral perfusion pressure. These lesions occurred in the absence of involvement of other brain regions considered selectively vulnerable to hypoxic insults. Hippocampal damage occurred in 46% of animals with mild injury characterized by brief periods of unconsciousness and no residual neurologic deficit. Ninety-four percent of animals with severe injuries and prolonged posttraumatic coma had hippocampal involvement. Traumatically induced selective neuronal necrosis of the hippocampus is a specific lesion not explained by the conventional mechanistic theories of head injury. An alternative hypothesis, such as excitotoxicity involving glutamate or other neurotransmitters, may account for the lesions demonstrated in this study.

Acceleration↗
PubMed1991

The microvascular response to stretch injury in the adult guinea pig visual system.

In a variety of brain injury models, both reactive axonal change and microvascular abnormalities occur. Development of a stretch injury model in the guinea pig optic nerve has allowed for the characterization of the early axonal response to injury. In this same model, we have now attempted to characterize those morphologic changes occurring in the visual system microvasculature after injury. Thirty adult guinea pigs were subjected to axonal stretch injury and killed at posttraumatic survival periods ranging from 10 minutes to 14 days. Twenty animals were examined by scanning electron microscopy (SEM) for the detection of posttraumatic changes in the surface morphology of the microvasculature, and 10 animals were processed for transmission electron microscopy (TEM) analysis. Through this approach, increased pit vesicle activity and formation of endothelial microvilli were recognized within 10 minutes of injury. Pit vesicle activity returned to control levels by 2 hours. The formation of endothelial microvilli was widespread, affecting the microvessels in both the stretched and unstretched optic nerves and in the chiasm. The greatest response developed most slowly in the stretched nerve, and it was faster but less marked in the unstretched nerve and chiasm. Microvilli were more numerous in larger vessels. Related astrocytic swelling/lucency was not apparent until 6 hours after injury. The astrocyte response was less marked than that documented after brain injury. The results of this investigation demonstrate a widespread microvascular response to stretch injury of the guinea pig optic nerve. Comparison with the documented responses to traumatic brain injury indicates different rates of response to different types of insult.

Animals↗
PubMed1991

Autoradiographic imaging of [3H]phorbol 12,13-dibutyrate binding to protein kinase C in Alzheimer's disease.

Quantitative autoradiography was used to examine the distribution of [3H]phorbol 12,13-dibutyrate ([3H]PDBu) binding to protein kinase C in the middle frontal and temporal cortices and the hippocampal region of nine control and nine elderly subjects with Alzheimer's disease (AD). AD patients had a clinical diagnosis of the disease that was confirmed neuropathologically by the presence of numerous plaques in the hippocampus and cerebral cortex. Choline acetyltransferase (ChAT) activity was significantly reduced in the middle frontal and temporal cortex and in the hippocampus of AD subjects, with the deficit being greater than 60% of control values. Quantitative autoradiographic analysis of [3H]PDBu binding to protein kinase C revealed a heterogeneous pattern in control brain, being particularly high in superficial layers of the cortex and CA1 of the hippocampus. There were no significant differences between control and AD sections in all areas examined within the middle frontal cortex; e.g., layers I-II control, 491 +/- 46 versus AD, 537 +/- 39 pmol/g of tissue; middle temporal cortex, e.g., layers I-II control, 565 +/- 68 versus AD, 465 +/- 72 pmol/g of tissue; and hippocampal formation, e.g., CA1 control, 511 +/- 28 versus AD, 498 +/- 25 pmol/g of tissue. In a parallel study, [3H]PDBu binding to homogenate preparations of control and AD brain confirmed that there was no significant difference in [3H]PDBu binding in either the particulate or the cytosolic fraction. We have demonstrated in a well-defined population of AD patients that [3H]PDBu binding to protein kinase C remains preserved in brain regions that are severely affected by the neuropathological and neurochemical correlates of AD.

Alzheimer Disease↗
PubMed1991

Glial swelling following human cerebral contusion: an ultrastructural study.

The ultrastructural features of cerebral contusion seen three hours to 11 days after head injury were studied in 18 patients undergoing surgery. Massive astrocytic swelling ("cytotoxic" oedema) was seen three hours to three days after injury, maximal in perivascular foot processes, and compressing some of the underlying capillaries. The tight junctions were not disrupted. Neuronal damage was most marked three to 11 days after injury. The pathophysiological mechanisms leading to oedema formation and neuronal degeneration are discussed.

Adult↗
PubMed1991

Ischemic neuronal damage after acute subdural hematoma in the rat: effects of pretreatment with a glutamate antagonist.

The ability of a competitive N-methyl-D-aspartate (NMDA) receptor antagonist (D-CPP-ene) to reduce irreversible brain damage has been examined in a rodent model of acute subdural hematoma. Acute subdural hematoma was produced by the slow injection of 400 microliters homologous blood into the subdural space overlying the parietal cortex in halothane-anesthetized rats. Brain damage was assessed histologically in sections at multiple coronal planes in animals sacrificed 4 hours after induction of the subdural hematoma. Pretreatment with D-CPP-ene (15 mg/kg) significantly reduced the volume of ischemic brain damage produced by the subdural hematoma from 62 +/- 8 cu mm (mean +/- standard error of the mean) in vehicle-treated control rats to 29 +/- 7 cu mm in drug-treated animals. These data demonstrate the anti-ischemic efficacy of NMDA antagonists in an animal model of intracranial hemorrhage in which intracranial pressure is elevated, and suggest that excitotoxic mechanisms (which are susceptible to antagonism by D-CPP-ene) may play a role in the ischemic brain damage which is observed in patients who die after acute subdural hematoma.

Animals↗
PubMed1991

Localisation of calcium ions and calcium-ATPase activity within myelinated nerve fibres of the adult guinea-pig optic nerve.

There is no published description of the distribution of free Ca2+, nor of the distribution of Ca(2+)-ATPase activity associated with the maintenance of low axoplasmic Ca2+ concentrations, in normal central myelinated nerve fibres. We have used the oxalate-pyroantimonate technique to localise free Ca2+, together with the lead-citrate technique to localise Ca(2+)-ATPase activity within myelinated fibres from the adult guinea-pig optic nerve. Pyroantimonate precipitate occurred within the axoplasm at nodes of Ranvier and the internode, at areas of myelin disruption, within Schmidt-Lanterman incisures (SLI) and glial paranodal loops. But precipitate was absent from the axoplasm beneath SLI and at the paranode. Ca(2+)-ATPase activity was localised in axonal smooth endoplasmic reticulum (SER), the outer membrane of mitochondria, the nodal axolemma, the glial membranes of the paranodal loops, the SLI and the external aspect of the myelin sheath. We have demonstrated large domains within the axons of CNS fibres where calcium is present or absent. Moreover, we have shown that, where calcium is absent, there is localisation of Ca(2+)-ATPase activity, which would serve to remove calcium from the adjacent axoplasm. Our results are compared with information obtained from PNS fibres and some differences of distribution discussed.

Animals↗
PubMed1991

Amelioration of delayed neuronal death in the hippocampus by nerve growth factor.

Selective neuronal death in the CA1 sector of the hippocampus [delayed neuronal death (DND)] develops several days after transient global cerebral ischemia in rodents. Because NGF plays a potential role in neuronal survival, it was decided to study its effect in DND. We report here that intraventricular injection of NGF either before or after 5 min forebrain ischemia in the Mongolian gerbil significantly reduced the occurrence of DND. The tissue content of NGF in the hippocampus was decreased 2 d after ischemia and recovered to the preischemic level by 1 week. By the Golgi staining technique, changes first began in the dendrites of affected neurons as early as 3 hr. Such changes could be ameliorated by NGF treatment. Although previous knowledge of NGF is limited to the survival of cholinergic neurons in the CNS, it is assumed that other mechanisms must be operating in the hippocampus, for example, postsynaptic modification at dendrites or aberrant expression of NGF receptors possibly at the initial excitation period by glutamate. Furthermore, because previous work has shown that inhibition of protein synthesis reduces the occurrence of DND, a program leading to cell death might also be operating via de novo synthesis of certain protein(s), collectively termed "killer protein," because of a lack of NGF.

Animals↗
PubMed1991

Pathological changes in the brains of mice infected with Toxoplasma gondii: a histological, immunocytochemical and ultrastructural study.

The pathological changes in the brains of mice infected with T. gondii were studied at various intervals between 7 days and 22 months post-infection using histology, immunocytochemistry and electron microscopy. Initially, a few single parasites were observed (day 7) but necrotic lesions and microglial and inflammatory nodules rapidly appeared (9-I4 days). The majority of the lesions between days 9 and I4 contained proliferating toxoplasma and early cyst formation but from 2I days onwards the vast majority of nodules contained neither parasites nor Toxoplasma antigen. Intact intracellular cysts persisted throughout the period of study eliciting no host response. A generalized meningoencephalitis developed by day II and persisted with varying degrees of severity throughout the 22 months studied. At first, the inflammatory cells consisted of lymphocytes and monocyte/macrophages but during the chronic phase plasma cells predominated. In chronic infections, the number of microglial/inflammatory nodules was relatively constant with only a few containing toxoplasmic material resulting from recent cyst rupture. A few brains contained small nodules of dystrophic calcification. This study shows that in these asymptomatic animals, the major feature is perivascular cuffing by mononuclear cells and localized microglial/inflammatory nodules. After the development of the chronic state, there is no obvious increase or decrease in the severity of the pathological changes with time.

Animals↗
PubMed1990

Reduction of delayed neuronal death by inhibition of protein synthesis.

Brief forebrain ischemia in rodents causes delayed neuronal death selectively in the CA1 pyramidal cells of hippocampus. Treatment with a reversible protein synthesis inhibitor, anisomycin, significantly reduced the occurrence of delayed neuronal death in the Mongolian gerbil. This result indicates that de novo synthesis of certain protein(s), collectively termed 'killer protein' is required, possibly due to deprivation of nerve growth factor or other trophic factors.

Animals↗
PubMed1990

Selective alterations of high affinity [3H]forskolin binding sites in Alzheimer's disease: a quantitative autoradiographic study.

Quantitative autoradiographic analysis of high affinity [3H]forskolin binding sites was carried out in postmortem brains from normal controls and patients dying with Alzheimer's disease. Choline acetyltransferase (ChAT) activity and senile plaque formation were also quantified. [3H]Forskolin binding was markedly reduced in all layers of middle frontal gyrus in the Alzheimer brains and the deficit correlated with the deficit in ChAT activity in this area. In the hippocampal region [3H]forskolin binding was no different in the Alzheimer brains compared to controls, although ChAT activity was significantly reduced. There was an inconsistent reduction in [3H]forskolin binding in all layers of middle temporal gyrus which did not correlate with the cholinergic deficit. Significant senile plaque formation was observed in all 3 brain regions examined and [3H]forskolin binding did not correlate with plaque formation in any brain region. Thus, while all 3 brain regions were affected by the pathological correlates of Alzheimer's disease, [3H]forskolin binding was consistently reduced only in frontal cortex.

Adenylyl Cyclases↗
PubMed1990

Selective reduction of quisqualate (AMPA) receptors in Alzheimer cerebellum.

Multiple sites involved in glutamatergic neurotransmission were examined in the cerebellar cortex of 6 patients with Alzheimer's disease and 6 age-matched control patients by using quantitative ligand-binding autoradiography. Quisqualate (AMPA) receptor binding was markedly reduced in the molecular layer of the cerebellum from patients with Alzheimer's disease (167 +/- 13 pmoles/gm) compared with control patients (280 +/- 13 pmoles/gm). In adjacent sections from the same patients and controls, there was preservation of kainate and N-methyl-D-aspartate receptor binding in the cerebellum from patients with Alzheimer's disease compared with control patients. Neuropathological examination of the cerebellar cortex revealed the presence of plaques and preservation of Purkinje cells in the patients with Alzheimer's disease.

Aged↗
PubMed1990

Blood-brain barrier damage in traumatic brain contusions.

Plasma proteins were used as an endogenous marker of blood-brain barrier damage in 19 patients dying with traumatic cortical contusions. Patients survived for a few hours to 31 days after head injury. Eight proteins (M WT 61-2,500 x 10(3) were demonstrated with standard immunohistochemical techniques. Proteins were not found in "control" brains or in macroscopically normal parasagittal cortex in the head injury patients. Proteins were found in all of the macroscopic contusion in all brains. Protein leakage appeared to be from the contusion itself. Protein staining around histologically normal vessels was unusual. There was a gradient of staining from the macroscopic contusion into the surrounding brain. There was a trend for staining to be most marked between 3 and 8 days survival after head injury. There was no gradient of leakage by molecular size of the protein.

Blood Proteins↗
PubMed1990

Ischaemic brain damage associated with tissue hypermetabolism in acute subdural haematoma: reduction by a glutamate antagonist.

Ischaemia results in elevated extracellular glutamate concentrations, and drugs which act at the N-methyl-D-aspartate sub-type of glutamate receptor have been shown to decrease ischaemic brain damage. Because almost all patients who die after severe head injury demonstrate ischaemic brain damage, and acute subdural haematoma (ASDH) is one of the commonest complications of severe head injury, we have studied this condition in a rat model. Using double-label autoradiography, we have measured the effects of ASDH on cerebral glucose utilization and cerebral blood flow (RCBF). Following ASDH, increased glucose utilisation was observed in some cortical and hippocampal structures, without concomitant increases in blood flow. Directly below the ASDH, blood flow and glucose utilization were profoundly reduced. Pre-treatment with D-CPP-ene, a competitive NMDA antagonist, resulted in amelioration of hypermetabolism induced by the ASDH. The results suggest that NMDA antagonists may prevent ischaemic brain damage after ASDH by reducing hypermetabolism, induced by glutamatergic mechanisms.

Acute Disease↗
PubMed1990

Glycogen accumulation in axons after stretch injury.

Thin-section cytochemistry has been used to demonstrate the formation of glycogen deposits within axons after stretch injury to the optic nerve of adult guinea pigs in a model of focal axonal injury. Glycogen deposits occurred within 17% of structurally normal but, we suggest, damaged fibres within the stretched optic nerve. Adjacent fibres did not stain for glycogen. Small numbers of beta glycogen particles were present 15 min after injury within damaged axons and increasing numbers of particles occurred until 72 h. Degeneration bulbs formed by 72 h, but beta glycogen particles were sparse within these. By 7-14 days after injury there was a marked reduction in the numbers of glycogen particles within axons. Alpha rosettes of glycogen were infrequent within damaged axons. Deposition of glycogen particles within astrocytes after nerve injury was confirmed. Alpha rosettes of glycogen occurred within astrocytes by 6 h and remained until 14 days after injury. Possible mechanisms for the development of glycogen deposits within damaged axons are discussed in relation to a hypothesized influx of Ca2+ at the time of injury into damaged axons. We suggest that glycogen deposition within reactive axons reflects Ca2+ mediated alteration of glycogen synthase activity and compromized axonal transport.

Animals↗
PubMed1990

5 HT2 receptors in dementia of Alzheimer type: a quantitative autoradiographic study of frontal cortex and hippocampus.

Using both quantitative autoradiography in sections and a homogenate preparation assay, the distribution and density of 3H-ketanserin binding to 5 HT2 receptors was examined in frontal cortex and the hippocampal region from six control subjects and seven subjects who had dementia of the Alzheimer type (DAT). There was no difference between control and DAT subjects in the levels of ketanserin binding in any region of the frontal cortex or hippocampus determined by quantitative autoradiography or in parallel experiments using homogenate preparations (e.g. left frontal cortex, layer III; controls, 34.4 +/- 1.6 pmol/g, DAT, 37.1 +/- 4.6 pmol/g). In all of the DAT brains there were abundant neuritic plaques (e.g. superficial layers of left frontal cortex; 35 +/- 7 plaques/mm2), and a marked reduction of choline acetyltransferase activity, (by 30-60% relative to controls), in both frontal cortex and the hippocampus. Thus, despite the presence of morphological abnormalities and a loss of cholinergic function, two classic features of DAT, 5 HT2 receptor binding was unaltered in this group of DAT brains compared to controls.

Alzheimer Disease↗
PubMed1990

Focal cerebral ischemia in the cat: pretreatment with a competitive NMDA receptor antagonist, D-CPP-ene.

The effects of the competitive N-methyl-D-aspartate (NMDA) receptor antagonist D-(E)-4-(3-phosphonoprop-2-enyl)piperazine-2-carboxylic acid (D-CPP-ene; SDZ EAA 494) upon ischemic brain damage have been examined in anesthetized cats. Focal cerebral ischemia was produced by permanent occlusion of the middle cerebral artery (MCA) and the animals were killed 6 h later. The amount of early ischemic brain damage was assessed in coronal sections at 16 predetermined stereotaxic planes. Pretreatment with D-CPP-ene (15 mg/kg i.v. followed by continuous infusion at 0.17 mg/kg/min until death), 15 min prior to MCA occlusion, significantly reduced the volume of ischemic brain damage (from 20.6 +/- 9.9% of the cerebral hemisphere in vehicle-treated cats to 7.2 +/- 4.4% in drug-treated cats; p less than 0.01). The competitive NMDA receptor antagonist D-CPP-ene is as effective as noncompetitive NMDA antagonists in reducing the amount of ischemic brain damage in this model of focal cerebral ischemia in a gyrencephalic species.

Animals↗
PubMed1990

Differential alterations of cortical glutamatergic binding sites in senile dementia of the Alzheimer type.

Involvement of cortical glutamatergic mechanisms in senile dementia of the Alzheimer type (SDAT) has been investigated with quantitative ligand-binding autoradiography. The distribution and density of Na(+)-dependent glutamate uptake sites and glutamate receptor subtypes--kainate, quisqualate, and N-methyl-D-aspartate--were measured in adjacent sections of frontal cortex obtained postmortem from six patients with SDAT and six age-matched controls. The number of senile plaques was determined in the same brain region. Binding of D-[3H]aspartate to Na(+)-dependent uptake sites was reduced by approximately 40% throughout SDAT frontal cortex relative to controls, indicating a general loss of glutamatergic presynaptic terminals. [3H]Kainate receptor binding was significantly increased by approximately 70% in deep layers of SDAT frontal cortex compared with controls, whereas this binding was unaltered in superficial laminae. There was a positive correlation (r = 0.914) between kainate binding and senile plaque number in deep cortical layers. Quisqualate receptors, as assessed by 2-amino-3-hydroxy-5-[3H]methylisoxazole-4-propionic acid binding, were unaltered in SDAT frontal cortex compared with controls. There was a small reduction (25%) in N-methyl-D-aspartate-sensitive [3H]glutamate binding only in superficial cortical layers of SDAT brains relative to control subjects. [3H]Glutamate binding in SDAT subjects was unrelated to senile plaque number in superficial cortical layers (r = 0.104). These results indicate that in the presence of cortical glutamatergic terminal loss in SDAT plastic alterations occur in some glutamate receptor subtypes but not in others.

Aged↗