Corpus callosum diffusion anisotropy correlates with neuropsychological outcomes in twins disconcordant for traumatic brain injury.

Conventional and diffusion tensor MR imaging studies in twins sustaining severe pediatric traumatic brain injury identified reduction in fractional anisotropy (FA) in all regions of the corpus callosum, particularly the posterior body, rostral body, and genu, relative to healthy cotwins. FA from the rostrum, genu, anterior body, posterior body, and isthmus were correlated with measures of reading speed and comprehension; verbal working memory and math fact retrieval scores were correlated only with the rostral body FA.

Cognitive and neuroimaging findings in physically abused preschoolers.

AIMS: To characterise the cognitive, motor, and language skills of toddlers and preschoolers who had been physically abused and to obtain concurrent MRIs of the brain. METHODS: A between groups design was used to compare a sample of 19 children, aged 14-77 months, who had been hospitalised for physical abuse with no evidence of neurological injury to a comparison group of 19 children matched for age and socioeconomic status. Children underwent cognitive, language, and motor testing within three months of their discharge from the hospital. Caregivers of the injured children were interviewed and were asked to complete questionnaires to characterise the child's developmental level and behaviour just prior to the hospitalisation. RESULTS: Children who had been physically abused scored significantly lower than the comparison group on measures of cognitive functioning, motor skills, and language skills. The groups did not differ in child behaviour ratings completed by the caregivers. MRI of the brain was performed for 15 children in the physical abuse group; two were found to have significant cerebral atrophy. CONCLUSIONS: Children who have been physically abused are at high risk for delays in cognitive, motor, and language development. Standard of care for these children should include developmental testing as well as neuroimaging of the brain to detect occult brain injury.

Recent perspectives in the design of antiasthmatic agents.

Asthma is a common respiratory disorder. It can no longer be viewed as a reversible airway obstruction but should instead be considered primarily as an inflammatory illness that has bronchial hyperreactivity and bronchospasm as its result. There are several potential benefits as well as limitations of the currently available antiasthmatic agents such as anticholinergics, beta 2-selective agonists, methylxanthines, corticosteroids, or mast cell stabilizers. Recent trends in the design of new antiasthmatic agents include isozyme selective phosphodiesterase inhibitors, inhibitors of the biosynthesis of interleukin-4 and IL-4 antagonists, lipoxygenase and leukotriene inhibitors, thromboxane A2 receptor antagonists, potassium channel openers and monoclonal antibodies.

Crush head injuries in infants and young children neurologic and neuropsychologic sequelae.

Neurologic and neuropsychologic sequelae of crush head injury, which is produced by static forces occurring when the head is stationary and pinned against a rigid structure, were studied prospectively in a series of eight children ranging in age from 13 to 32 months. Hospital course, computed tomographic findings, and neurologic and developmental outcomes were examined. All children sustained pronounced cerebral trauma characterized by multiple fractures throughout the calvaria, extra-axial hemorrhages, and parenchymal contusions. Cranial nerve injuries were noted in three and hemiparesis in two of the cases. Two months after the injury, 63% of the children displayed deficits in either IQ or motor functioning. One year after the injury, five of the six children reevaluated had a good recovery. Motor scores were significantly lower than cognitive scores at baseline and showed the greatest degree of improvement over time. Neuropsychologic outcome after brain injury produced by static loading of the head is more favorable than from traumatic brain injury associated with dynamic loading.

Severity of experimental brain injury on lactate and free fatty acid accumulation and Evans blue extravasation in the rat cortex and hippocampus.

Lactate and free fatty acids (FFAs) were extracted from the cortices and hippocampi of rats subjected to sham operation, or mild (1.25 atm) or moderate (2.0 atm) fluid percussion (FP) injury, and their total tissue concentrations were measured. The elevation of lactate in the injured left cortex (IC) and ipsilateral hippocampus (IH) was significantly greater in the moderate-injury than in the mild-injury group at most test times between 5 min and 48 h after injury. Levels of total FFAs were elevated in the IC and IH to a greater extent and for a longer period after injury in the moderate-injury (up to 48 h) than in the mild-injury group (up to 20 min). In general, the extent and duration of the elevation of most of the individual FFAs (palmitic, stearic, oleic, and arachidonic acids) in the IC and IH were also greater in the moderate-injury group than in the mild-injury group. In the contralateral cortex (CC) and hippocampus (CH), the elevation of lactate and total FFAs (and individual stearic and arachidonic acids) were also greater in the moderate-injury group than in the low-injury group at 5 min after injury. The extravasation of Evans blue in the IC and IH from 3 to 6 h after injury was also the greatest in the moderate-injury group. The hippocampal CA3 neuronal cell loss, but not cortical lesion volume, also increased with the severity of injury. These findings suggest that certain neurochemical, physiological (blood-brain barrier permeability), and morphologic responses increase with the severity of FP brain injury, and such relationships are consistent with the increased behavioral deficits observed with the increase of severity of brain injury.

Alterations in BDNF and trkB mRNA levels in the cerebral cortex following experimental brain trauma in rats.

Recent studies have suggested that brain-derived neurotrophic factor (BNDF) and its receptor, trkB, may provide neuroprotection following injury to the central nervous system. Conversely, other studies have implicated BDNF as a contributing factor to neurodegenerative events that occur following injury. In order to further investigate the role of BDNF in neuroprotection, we subjected adult rats to a lateral fluid percussion (FP) injury of moderate severity (2.0-2.1 atm) or sham injury. After survival periods of 1, 3, 6, 24, or 72 h, the brains were processed for the in situ hybridization localization of BDNF and trkB mRNAs using 35S-labeled cRNA probes. Hybridization levels were compared between injured and sham animals for regions of the cortex that were located within, adjacent to, and remote from the site of the cortical contusion. BDNF mRNA levels were significantly decreased in the injured cortex at 72 h, increased in adjacent cortical areas at 3 h, and increased bilaterally in the piriform cortex from 3 to 24 h post-FP injury. Expression of trkB mRNA was significantly decreased at all postinjury time-points in the injured cortex and at 24 h in the adjacent cortex. These results demonstrate that, following lateral FP injury, BDNF and trkB mRNA levels are decreased in cortical regions that contain degenerating neurons, generally unchanged in adjacent regions, and increased in remote areas. Thus, injury-induced decreases in the expression of BDNF and trkB may confer vulnerability to neurons within the cortical contusion.

Regional levels of brain phospholipase Cgamma in Alzheimer's disease.

The levels of PLCgamma, a phospholipase C (PLC) isozyme, were higher in the cytosol fraction than in the membrane fraction in several control brain regions. The levels of PLCgamma were significantly elevated in the membrane, but not in the cytosolic fraction of the hippocampus of AD subjects. In the superior and middle temporal gyri (SMTG) of AD subjects, the levels of PLCgamma were significantly elevated in both the membrane and cytosolic fractions. In the inferior parietal lobule and cerebellum of AD subjects, no significant changes were found in the PLCgamma levels of either cytosolic or membrane fractions. These results suggest that the increased levels of PLCgamma, by increasing the hydrolysis of PIP2 in the hippocampus and SMTG, may contribute to pathophysiology of AD. These results also support a role for excitatory neurotransmitters and their receptors in AD.

Expression of trkB mRNA is altered in rat hippocampus after experimental brain trauma.

Recent investigations have shown that expression of mRNAs for the neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) is differentially altered in the hippocampus following traumatic brain injury. In the present study, modulation of neurotrophin receptor expression was examined in the hippocampus in a rat model of traumatic brain injury using in situ hybridization. Messenger RNA for trkB, the high-affinity receptor for BDNF and neurotrophin-4 (NT-4), was increased between 3 and 6 h bilaterally in the dentate gyrus following a lateral fluid-percussion brain injury of moderate severity (2.0-2.1 atm). No time-dependent alterations were observed for trkB mRNA in hippocampal subfields CA1 and CA3. Levels of mRNA for trkC, the high-affinity receptor for NT-3, did not change in any region of the hippocampus. These data demonstrate that lateral fluid-percussion injury modulates expression of trkB mRNA in the hippocampus and support a role for BDNF/trkB signalling mechanisms in secondary events associated with traumatic brain injury.

Regional membrane phospholipid alterations in Alzheimer's disease.

Regional levels of membrane phospholipids [phosphatidylethanolamine (PE), phosphatidylinositol (PI), phosphatidylcholine (PC)] were measured in the brain of Alzheimer's disease (AD) and control subjects. The levels of PE-derived and PI-derived total fatty acids were significantly decreased in the hippocampus of AD subjects. Here significant decreases were found in PE-derived stearic, oleic and arachidonic and docosahexaenoic acids, and in PI-derived oleic and arachidonic acids. In the inferior parietal lobule of AD subjects, significant decreases were found only in PE and those decreases were contributed by stearic, oleic and arachidonic acids. In the superior and middle temporal gyri and cerebellum of AD subjects, no significant decreases were found in PC-, PE- and PI-derived fatty acids. The decrease of PE and PI, which are rich in oxidizable arachidonic and docosahexaenoic acids, but not of PC, which contains lesser amounts of these fatty acids, suggests a role for oxidative stress in the increased degradation of brain phospholipids in AD.

Alterations in BDNF and NT-3 mRNAs in rat hippocampus after experimental brain trauma.

Previous studies have suggested that the neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) are neuroprotective or neurotrophic for certain subpopulations of hippocampal neurons following various brain insults. In the present study, the expression of BDNF and NT-3 mRNAs in rat hippocampus was examined after traumatic brain injury. Following lateral fluid percussion (FP) brain injury of moderate severity (2.0-2.1 atm) or sham injury, the hippocampi from adult rats were processed for the in situ hybridization localization of BDNF and NT-3 mRNAs using 35S-labeled cRNA probes at post-injury survival times of 1, 3, 6, 24 and 72 h. Unilateral FP injury markedly increased hybridization for BDNF mRNA in the dentate gyrus bilaterally which peaked at 3 h and remained above control levels for up to 72 h post-injury. A moderate increase in BDNF mRNA expression was also observed bilaterally in the CA3 region of the hippocampus at 1, 3, and 6 h after FP injury, but expression declined to control levels by 24 h. Conversely, NT-3 mRNA was significantly decreased in the dentate gyrus following FP injury at the 6 and 24 h survival times. These results demonstrate that FP brain injury differentially modulates expression of BDNF and NT-3 mRNAs in the hippocampus, and suggest that neurotrophin plasticity is a functional response of hippocampal neurons to brain trauma.

Time course of changes in lactate and free fatty acids after experimental brain injury and relationship to morphologic damage.

Regional levels of lactate and free fatty acids (FFA) were measured after lateral fluid percussion (FP) brain injury in rats. At 5 min after injury, tissue concentrations of lactate were elevated in the cortices and hippocampi of both ipsilateral and contralateral hemispheres. Whereas lactate levels had returned to normal by about 20 min after injury in the penumbra and contralateral cortices, their elevation persisted in the ipsilateral injured cortex and hippocampus for 24 h after injury. Increases in the levels of FFA (particularly stearic and arachidonic acids) were observed in the cortices and hippocampi of both ipsilateral and contralateral hemispheres at 5 min after injury; these levels returned to normal in only the penumbra and contralateral cortices by 20 min after injury. Increased amounts of palmitic and oleic acids were also found only in the injured left cortex and ipsilateral hippocampus at 20 min or later after injury. In general, these elevations persisted for as long as 6 to 24 h in the injured cortex and for 2.5 to 24 h after injury in the ipsilateral hippocampus. Histologic studies revealed a similar extent of damage in the cortex between 5 min and 24 h after injury, whereas damage in the CA3 region of the ipsilateral hippocampus increased during that period. These findings suggest a role for lactic acid and FFA, two secondary injury factors, in neuronal cell loss after brain injury.

Protective effects of ifenprodil on ischemic injury size, blood-brain barrier breakdown, and edema formation in focal cerebral ischemia.

OBJECTIVE: Ifenprodil, a polyamine site N-methyl-D-aspartate receptor/channel antagonist, has been reported to decrease infarction volume after cerebral ischemia. However, the possible mechanisms of this protective effect have not been studied in detail. We investigated the effects of ifenprodil on ischemic injury size, blood-brain barrier (BBB) permeability, regional brain edema, and cerebral blood flow. METHODS: Focal ischemia for 6 hours was produced by permanent occlusion of the middle cerebral artery in 15 anesthetized cats. Treatment with drug (n = 8) or vehicle (n = 7) was initiated at 5 minutes after ischemia and continued for 3 hours. Physiological variables were continuously monitored during experiments. We measured ischemic injury size, brain edema, and BBB permeability to Evans blue and determined regional cerebral blood flow by using laser doppler flowmetry. RESULTS: Both ischemic injury size and BBB permeability were smaller in the ifenprodil-treated group, compared with the saline-treated group (P < 0.05). Ifenprodil treatment also attenuated brain edema formation in the dense ischemic region, compared with saline treatment (1.035 +/- 0.002 versus 1.028 +/- 0.002, P < 0.05). There was no significant change in cerebral blood flow with ifenprodil treatment. CONCLUSION: Findings from this study confirm that ifenprodil treatment results in a significant decrease in the size of ischemic injury after focal ischemia. The tissue-sparing effect of ifenprodil is not related to its vasoactive properties. It is likely that its neuroprotective effects are related to its ability to antagonize N-methyl-D-aspartate receptors, which results in a decrease in brain edema and BBB permeability.

Effect of hyperglycemia on reperfusion-associated recovery of intracellular pH and high energy phosphates after transient cerebral ischemia in gerbils.

Hyperglycemia increases cerebral damage after transient cerebral ischemia. This study used in vivo 31P nuclear magnetic resonance spectroscopy to determine the relationship of intracellular tissue acidosis and delayed recovery of brain high-energy phosphates to increased damage during the reperfusion period. Mongolian gerbils were subjected to transient bilateral carotid ischemia for 20 min with 2 h reperfusion. All gerbils were pretreated intraperitoneally with equivalent volumes in saline of 0.003 units per kilogram of insulin or vehicle, or with 4 grams of glucose per kilogram. The gerbils were then scanned in a 4.7 Tesla Magnetic Resonance Imager-Spectrometer to determine levels of intracellular pH, inorganic phosphate, adenosine triphosphate, and phosphocreatine. In each group, intracellular pH decreased with ischemia, but most significantly in hyperglycemic animals (6.45 +/- 0.15), in which it had not recovered to preischemic levels by the end of the reperfusion period (6.8 +/- 0.1 vs 7.04 +/- 0.1, p < 0.05). High-energy phosphates phosphocreatine-inorganic phosphate and phosphocreatine-adenosine triphosphate showed partial recovery in all groups throughout the reperfusion period; the recovery was not significantly altered by glucose status. Hyperglycemia worsened pH but not the recovery of high-energy phosphates in animals reperfused after 20 min of transient cerebral ischemia. This sustained acidosis may be a primary event in transient damage in hyperglycemic animals.

Regional generation of leukotriene C4 after experimental brain injury in anesthetized rats.

Regional concentrations of leukotriene C4 and extravasation of Evans blue were measured after lateral fluid-percussion brain injury in rats. Tissue levels of LTC4 were elevated in the injured cortex at 10 min, 30 min, and 1 h after injury; these levels returned to normal by 2 h after injury. Increases in the levels of LTC4 were also observed in the ipsilateral hippocampus after brain injury, and these elevations persisted for 2 h after injury. No significant increase in levels of LTC4 was observed in the contralateral cortex at any time after injury. A substantial extravasation of Evans blue was observed only in the ipsilateral cortex and hippocampus at 3 h and 6 h after brain injury. Although a temporal association between LTC4 and blood-brain barrier (BBB) breakdown is suggested by these data, no cause-and-effect relationship has been addressed in this study. However, it is possible that, as is true for cerebral ischemia, LTC4 may play a role as a mediator in the BBB breakdown associated with fluid-percussion brain injury in rats.

Effects of muscarinic receptor antagonism on the phosphatidylinositol bisphosphate signal transduction pathway after experimental brain injury.

Hippocampal levels of fatty acids extracted from phosphatidylinositol 4,5-bisphosphate (PIP2), free fatty acids (FFA), and lactate were measured after central fluid percussion traumatic brain injury (TBI) in rats. At 5 min after injury, there was a decrease in fatty acids extracted from PIP2 suggesting a decrease in PIP2. At the same time point, total FFA increased in saline-treated TBI rats. Levels of arachidonic acid were significantly decreased in PIP2, while at the same time arachidonic and stearic acids increased in FFA in saline-treated TBI rats. No significant alterations in PIP2-derived fatty acids or FFA were observed at 20 min after TBI. Hippocampal concentrations of lactate were significantly elevated at 5 and 20 min after injury in saline-treated rats. In general, these alterations were blunted by preinjury administration of the muscarinic antagonist, scopolamine. These results suggest that the PIP2 signal transduction pathway is activated in the hippocampus at the onset of central fluid percussion TBI and that the enhanced phospholipase C-catalyzed phosphodiestric breakdown of PIP2 is a major mechanism of liberation of FFA in these sites immediately after such injury. The blunting of PIP2 and FFA alterations in animals treated with scopolamine suggests that activation of muscarinic receptors significantly contributes to the phospholipase C (PLC) signal transduction pathophysiology in TBI. The attenuation of lactate accumulation in scopolamine-treated rats suggests that TBI-induced muscarinic receptor activation also contributes to increased glycolytic metabolism and/or ionic imbalances.

Protective effect of the 5-lipoxygenase inhibitor AA-861 on cerebral edema after transient ischemia.

This study examined the effect of AA-861, a specific 5-lipoxygenase inhibitor, on brain levels of leukotriene C4 (LTC4) and correlated any changes with changes in edema formation and cerebral blood flow (CBF) after transient ischemia in gerbils. Brain levels of LTC4 were observed to be increased at 1, 2, and 6 hours of reperfusion following 20 minutes of occlusion. At 2 hours of reperfusion, a pretreatment dose of 1000 mg/kg of AA-861 was required to inhibit more than 90% of the reperfusion-induced increases in brain LTC4. At this dose, inhibition of LTC4 production was observed at 2 and 6 hours of reperfusion. The specific gravity of both the cortex and subcortex was decreased at 6 hours of reperfusion after 20 minutes of occlusion. At 2 hours of reperfusion, no significant difference was observed in the specific gravity of the cortex and subcortex regions of gerbils pretreated with AA-861 or with vehicle, but at 6 hours of reperfusion significant positive differences were observed. Cerebral blood flow decreased to approximately 10% of preocclusion values during occlusion and returned to near-preocclusion values after 10 minutes of reperfusion. No significant differences were observed in regional CBF in the AA-861- and vehicle-pretreated gerbils during reperfusion. These findings indicate that LTC4 production after transient cerebral ischemia may be an important contributor to the development of cerebral edema and that CBF does not mediate the LTC4-involved development of edema.

Alterations in brain protein kinase C after experimental brain injury.

Regional activities and levels of protein kinase C were measured after lateral fluid percussion brain injury in rats. At 5 min and 20 min after injury, neither cofactor-dependent nor -independent PKC activities in the cytosol and membrane fractions changed in the injured and contralateral cortices or in the ipsilateral hippocampus. Western blot analysis revealed decreases in the levels of cytosolic PKC alpha and PKC beta in the injured cortex after brain injury. In the same site, a significant increase in the levels of membrane PKC alpha and PKC beta was observed after injury. Although the level of PKC alpha did not change and that of PKC beta decreased in the cytosol of the ipsilateral hippocampus, these levels did not increase in the membrane fraction after injury. The levels of PKC gamma were generally unchanged in the cytosol and the membrane, except for its decrease in the cytosol of the hippocampus. There were no changes in the levels of any PKC isoform in either the cytosol or the membrane of the contralateral cortex after injury. The present results suggest a translocation of PKC alpha and PKC beta from the cytosol to the membrane in the injured cortex after brain injury. The observation that such a translocation occurs only in the brain regions that undergo substantial neuronal loss suggests that membrane PKC may play a role in neuronal damage after brain injury.

Enhanced accumulation of free fatty acids in experimental focal cerebral ischemia.

Cerebral ischemia is well known to cause an increase in the level of free fatty acids (FFAs) in rodent species. Such FFA accumulations may signal regional lipid membrane damage and are postulated to participate in the pathogenesis of progressive infarction after cerebral ischemia. In this study we have examined the regional levels of FFAS in the cortices of cats after 8 h of middle cerebral artery occlusion. The levels of specific FFAs (palmitic, stearic, and oleic acids) were 1.5 and 2.0 times higher in the penumbral and dense ischemic regions, respectively, than those in the non-ischemic contralateral region. Although no significant differences were found between the penumbra and dense ischemic regions in the levels of arachidonic acid, the levels of docosahexaenoic acid in both of these regions were significantly higher than those in the contralateral region (P < 0.05). These results suggest that enhanced accumulation of FFAs are regionally distributed after focal ischemia and may contribute to neuronal damage after focal cerebral ischemia in non-rodent species.

Effect of difluoromethylornithine treatment on regional ornithine decarboxylase activity and edema formation after experimental brain injury.

This study examined the effect of difluoromethylornithine (DFMO) on regional activities of ornithine decarboxylase (ODC) and edema formation in bilateral cerebral cortex and hippocampus after a unilateral controlled cortical-impact (CCI) injury in rats. To measure the activity of ODC, the brains of injured and control rats were frozen in situ at 30 min, 3, 6, and 24 h after CCI brain injury of moderate severity. The specific gravity, an indicator of edema formation, was examined in decapitated animals at corresponding time points. Brain injury induced significant increases of ODC in the ipsilateral hippocampus, adjacent and injury-site cortices, and in the contralateral cortex and hippocampus at 3 and 6 h after injury. No significant edema formation was found in any brain region at 30 min after injury. A significant edema formation was first found only in the injury-site cortex at 3 h after injury. At 6 and 24 h after injury, significant edema was found in all regions ipsilateral to the injury-site. At 24 h after injury, significant but less severe edema was also found in the contralateral cortex and hippocampus. DFMO, an irreversible inhibitor of ODC, abolished the increase in ODC in all regions. It also attenuated edema formation in the adjacent cortex and in the contralateral cortex and hippocampus. These findings indicate that polyamines may play a role in posttraumatic brain edema formation, particularly in important brain regions remote from the injury-site.