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PubMed1999

Is traumatic axonal injury (AI) associated with an early microglial activation? Application of a double-labeling technique for simultaneous detection of microglia and AI.

The aim of the present study was to determine whether axonal injury (AI) induces a microglial reaction within 15 days after brain trauma. In 40 selected cases of confirmed AI, the topographical relation of AI and microglial reaction was assessed using an immunohistochemical double-labeling technique for simultaneous demonstration of AI using beta-amyloid precursor protein (beta-APP) antibody and of microglia using CD68 antibody. Although traumatic injury was usually followed by a moderate early diffuse rise in the number of CD68-reactive cells in the white matter, increases in macrophages in areas of AI accumulation were only sporadic and did not occur until after 4 days. At survival intervals of 5-15 days a moderate microglial reaction in regions of beta-APP-positive injured axons was detected, at maximum, in half of the case material. During this interval AI-associated satellitosis-like clusters or stars described by other authors after a survival time of more than 7 weeks were an isolated phenomenon. The prolonged microglial reaction as well as the reduction of beta-APP-positive AI during longer survival periods supports the hypothesis that AI is not primarily chemotactically attractive and that the damage to a portion of beta-APPstained axons may be partly reversible. Most cases clearly require a prolonged interval of more than 15 days before initiation of the final scavenger reaction. For forensic purposes the increase in the number of microglial cells within the region of AI accumulation after a survival time of more than 5 days and the multiple and distinct demonstration of star-like microglial reactions within the white matter after survival times exceeding 7 weeks may provide valuable postmortem information on the timing of a traumatic event.

Adolescent↗
PubMed2001

Axonal metabolic recovery in multiple sclerosis patients treated with interferon beta-1b.

Patients with multiple sclerosis (MS) can benefit from treatment with interferon beta-1b. However, the mechanisms of action of this drug are incompletely understood and effects of interferon beta-lb on axonal injury are not known. A measure of axonal injury can be obtained in vivo using magnetic resonance spectroscopy to quantify the resonance intensity of the neuronal marker, N-acetylaspartate (NAA). In a small pilot study, we performed combined magnetic resonance imaging and magnetic resonance spectroscopic imaging on 10 patients with relapsing-remitting MS before and 1 year after starting treatment with subcutaneous interferon beta-lb. Resonance intensities of NAA relative to creatine (Cr) were measured in a large, central brain volume. These measurements were compared with those made in a group of 6 untreated patients selected to have a similar range of scores on the Expanded Disability Status Scale and mean NAA/Cr at baseline. NAA/Cr in the treated group [2.74 (0.16), mean (SD)] showed an increase of 5.5% 12 months after the start of therapy [2.89 (0.24),p = 0.05], while NAA/Cr in the untreated group decreased, but not significantly [2.76 (0.1) at baseline, 2.65 (0.14) at 12 months,p > 0.1]. NAA/Cr had become significantly higher in the treated group at 12 months than in the untreated group (p = 0.03). Our data suggest that, in addition to losing axons, patients with chronic multiple sclerosis suffer from chronic, sublethal axonal injury that is at least partially reversible with interferon beta-lb therapy.

Adjuvants, Immunologic↗
PubMed2004

Effect of mild hypothermia on brain dialysate lactate after fluid percussion brain injury in rodents.

OBJECTIVE: To investigate the effects of mild hypothermia on brain microdialysate lactate after fluid percussion traumatic brain injury (TBI) in rats. METHODS: Brain dialysate lactate before and after fluid percussion brain injury (2.1 +/- 0.2 atm) was measured in rats with preinjury mild hypothermia (32 degrees C), postinjury mild hypothermia (32 degrees C), injury normothermia (37 degrees C), and the sham control group. Mild hypothermia (32 degrees C) was induced by partial immersion in a water bath (0 degrees C) under general anesthesia and maintained for 2 hours. RESULTS: In the normothermia TBI group, brain extracellular fluid lactate increased from 0.311 +/- 0.03 to 1.275 +/- 0.08 mmol/L within 30 minutes after TBI (P < 0.01) and remained at a high level (0.546 +/- 0.05 mmol/L) (P < 0.01) at 2 hours after injury. In the postinjury mild hypothermic group, brain extracellular fluid lactate increased from 0.303 +/- 0.03 to 0.875 +/- 0.05 mmol/L at 15 minutes after TBI (P < 0.01) and then gradually decreased to 0.316 +/- 0.04 mmol/L at 2 hours after TBI (P > 0.05). In the preinjury mild hypothermic group, brain extracellular fluid lactate remained at normal levels after injury (P > 0.05). CONCLUSION: The cerebral extracellular fluid lactate level increases significantly after fluid percussion brain injury. Preinjury mild hypothermia completely inhibits the cerebral lactate accumulation, and early postinjury mild hypothermia significantly blunts the increase of cerebral lactate level after fluid percussion injury.

Animals↗
PubMed2005

Novel aspects of the neuropathology of the vegetative state after blunt head injury.

A detailed neuropathological study was undertaken of the brains of patients who had been assessed clinically as vegetative after blunt head injury. There were 35 cases, (33 male; median age 38 years) with a survival of 6.5-19 months (median 9): 17 were injured in a road traffic accident, 9 after assault and 6 after a fall; 3 were recorded as having had a lucid interval. There was an intracranial hematoma in 9 and the median contusion index was 4; raised intracranial pressure was identified in 25, grades 2 and 3 diffuse traumatic axonal injury was present in 25, ischemic damage in 15 and hydrocephalus in 27. Thalamic and hippocampal damage was present in 28 and stereological studies revealed a differential loss of neurons in three principal nuclei of the thalamus and in different sectors of the hippocampus. Immunohistochemistry provided evidence of an inflammatory reaction and in situ DNA fragmentation, features that are strongly indicative of a continuing neuronal loss in subcortical gray matter. These findings provide evidence for the importance of diffuse brain damage to white matter as the structural basis of the vegetative state after blunt head injury with contributions from neuronal loss in the thalami and the hippocampus. Although amyloid plaques and tau inclusions were identified in some, their contribution did not seem important in the ultimate clinical outcome.

Adult↗
PubMed2001

[Differences in immunohistochemical findings in traumatic and hypoxic changes in the central nervous system].

The authors made in a group of deceased subjects with craniocerebral injuries and subjects with protracted hypoxia without mechanical brain injury immunohistochemical investigations of neuron-specific enolase and beta-amyloid protein precursor. Neuron-specific enolase (NSE) is produced by nerve cells and is a suitable marker of neuron as well as axon damage. While the bodies of intact nerve cells display immunoreactivity with the anti-NSE antibody, in damaged neurons already within two hours after injury a marked drop of this protein substance was observed after mechanical injury as well as after protracted hypoxia. In axons altered by injury the authors observed the presence of NSE already within several tens of minutes after injury while hypoxia of the brain without mechanical injury did not produce any or only a very weak reaction of axons on examination with anti-NSE without a topographic link to the axonal lesion. Beta-amyloid protein precursor (beta-APP) is a low molecular protein the normal values of which are not detectable in axons by standard immunochemistry. In axons altered by injury the authors observed an increased incidence of this protein substance while in cerebral hypoxia without mechanical injury of the CNS only in rare instances a positive reaction with anti-beta-APP antibody was found.

Adolescent↗
PubMed2003

Impact mechanics and axonal injury in a sheep model.

This paper describes a biomechanical study of axonal injury due to a blunt impact to the head. The aim of the experimental model was to produce axonal injury analogous to that seen in human trauma while measuring the dynamics of the impact and the subsequent kinematics of the head. These measurements were made in a way to facilitate the simulation of these experiments using the finite element method. Sheep were anaesthetised and ventilated, and subjected to a single impact to the lateral aspect of their skull. The impact force was measured throughout the duration of the impact and the kinematics of the head was measured using a novel implementation of a nine-accelerometer array. The axonal injury was identified using amyloid precursor protein (APP) as a marker, intensified using antigen retrieval techniques. Axonal injury was consistently produced in all animals. Commonly injured regions included the sub-cortical and deep white matter, and the periventricular white matter surrounding the lateral ventricles. The observed axonal injury was mapped and quantified on three coronal sections of each brain. The measure used to describe the injury severity correlated with the peak magnitude of the impact force and with peak values of kinematic parameters, particularly the peak change of linear and angular velocity.

Animals↗
PubMedDate not supplied

Expression and role of low-affinity nerve growth factor receptor (p75) in spinal motor neurons of aged rats following axonal injury.

Expression of low-affinity nerve growth factor receptor (p75) and its regulation in spinal motor neurons of aged rats following axonal injury were investigated by immunocytochemical staining with antibody against p75. Under normal conditions, approximately 60% of spinal motor neurons expressed p75 in aged rats whereas no p75 expression was observed in spinal motor neurons of young adult rats. We examined the effects of spinal motor neuron injury on aged rats by two approaches, i.e. distal axotomy and spinal nerve root avulsion. A 20% increase in the number of p75-positive motor neurons was observed in aged rats 2 weeks after distal axotomy after which it returned to normal by 8 weeks post-injury and remained constant. Following root avulsion, a transient and slight up-regulation of p75 expression was observed in injured motor neurons. The number of p75-positive motor neurons decreased quickly to below normal levels 1 week after lesion and progressively declined with time post-injury, 40% by 2 weeks, 33% by 4 weeks, 23% by 8 weeks, and 5.8% by 12 weeks compared with the normal controls. This study demonstrates that p75 is re-expressed in aged spinal motor neurons. Following axonal injury in aged rats, up-regulation of p75 seems to coincide with the survival of injured motor neurons. Potential roles of re-expression of p75 in aged motor neurons are discussed.

Aging↗
PubMed2000

Magnetization transfer imaging in the detection of injury associated with mild head trauma.

BACKGROUND AND PURPOSE: Most traumatic brain injuries are classified as mild, yet in many instances cognitive deficits result. The purpose of this study was to investigate possible relationships between quantitative magnetization transfer imaging (MTI) and neurocognitive findings in a cohort of patients with mild head trauma but negative findings on conventional MR images. METHODS: We examined 13 patients and 10 healthy volunteers with a standard MR protocol including fast spin-echo and gradient-echo imaging, to which was added quantitative MTI. MTI was performed with a modified gradient-echo sequence incorporating pulsed, off-resonance saturation. Both region-of-interest analysis and contour plots were obtained from the MTI data. A subgroup of nine patients was examined with a battery of neuropsychological tests, comprising 25 measures of neurocognitive ability. RESULTS: The magnetization transfer ratio (MTR) in the splenium of the corpus callosum was lower in the patient group as compared with the control group, but no significant reduction in MTR was found in the pons. Individual regional MTR values were significantly reduced in two cases, and contour plot analysis revealed focal areas of abnormality in the splenium of four patients. All the patients showed impairment on at least three measures of the neuropsychological test battery, and in two cases a significant correlation was found between regional MTR values and neuropsychological performance. CONCLUSION: Our results suggest that MTI and contour plot analysis may add sensitivity to the MR imaging examination of patients with traumatic brain injury.

Adult↗
PubMed2005

Selective induction of ultrastructural (neurofilament) compaction in axons by means of a new head-injury apparatus.

A new weight-drop head-injury apparatus is described that can produce a momentary depression of predetermined depth at a predetermined site of the elastic calvaria of scalped young adult rats. In Wistar rats weighing about 200 g, a 0.75-mm deep calvaria depression immediately caused ultrastructural (neurofilament) compaction in many long axon segments, which were diffusely scattered among non-compacted axons in a well-defined area of cortical layers IV and V under the impact site. Apart from these morphological changes and swollen astrocytic processes in their vicinity, the brain tissue appeared non-impaired. The blood pressure, intracranial pressure, heart rate and respiration rate had returned to the normal range in 1 min. Diffuse axonal swelling caused by impaired axonal transport, ultrastructural compaction in neuronal soma-dendrite domains, impression fracture and subarachnoid or subdural hemorrhages were observed only in rats with a calvaria depression of 1mm or more. All these features create favorable circumstances for study of various problems that are closely related to the ultrastructural (neurofilament) compaction in axons, such as the fate of the affected axons.

Amyloid beta-Protein Precursor↗
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↗
PubMed2002

Which CT features help predict outcome after head injury?

BACKGROUND: Information collected at baseline can be useful in predicting patient outcome after head injury. The appearance of the CT brain scan may add useful baseline information. The aim of this study was to evaluate which features on the admission CT scan might add significantly to other baseline clinical information for predicting survival in patients with head injury. METHODS: Baseline CT scans were reviewed for patients with all grades of traumatic head injury in a head injury registry, in which baseline demographic and injury status and outcome at 1 year were recorded. Details from the CT scan on haemorrhage, brain swelling, and focal or diffuse damage were noted blind to clinical or outcome information and the scans classified according to the simple seven point grading (normal, mild, moderate, or severe focal injury, mild, moderate, or severe diffuse injury). An existing CT scoring system, the trauma coma databank (TCDB) classification, was also used. Logistic regression modelling was used to test the value of the CT appearance, in addition to the other baseline clinical characteristics, in predicting survival at 1 year. RESULTS: 425 CT scans were read from patients with all severities of injury. Significant independent outcome predictors were age, Glasgow coma score (GCS), pupil reaction, presence of subarachnoid blood, and the simple grading of the overall appearance of the scan (all p<0.001). The TCDB classification was not a significant predictor of outcome. CONCLUSION: Age, GCS, and pupil reaction were all previously shown to be significant predictors of patient survival after head injury. A further two, easy to identify, CT scan variables are independent prognostic variables, and might help to identify patients at high risk of death at the time of admission.

Brain Damage, Chronic↗
PubMed2003

Traumatic axonal injury results in biphasic calpain activation and retrograde transport impairment in mice.

Traumatic axonal injury (TAI) is one of the most important pathologies associated with closed head injury, and contributes to ensuing morbidity. The authors evaluated the potential role of calpains in TAI using a new model of optic nerve stretch injury in mice. Male C57BL/6 mice were anesthetized, surgically prepared, and subjected to a 2.0-mm optic nerve stretch injury (n = 34) or sham injury (n = 18). At various intervals up to 2 weeks after injury, optic nerves were examined for neurofilament proteins and calpain-mediated spectrin breakdown products using immunohistochemistry. In addition, fluorescent tracer was injected into the superior colliculi of mice 1 day before they were killed, to investigate the integrity of retrograde axonal transport to the retina. Optic nerve stretch injury resulted in persistent disruption of retrograde axonal transport by day 1, progressive accumulation and dephosphorylation of neurofilament protein in swollen and disconnected axons, and subsequent loss of neurofilament protein in degenerating axons at day 14. Calpains were transiently activated in intact axons in the first minutes to hours after stretch injury. A second stage of calpain-mediated proteolysis was observed at 4 days in axonal swellings, bulbs, and fragments. These data suggest that early calpain activation may contribute to progressive intraaxonal structural damage, whereas delayed calpain activation may be associated with axonal degeneration.

Animals↗
PubMed2000

Mechanism responsible for the formation of focal swellings on injured neuronal processes using a novel in vitro model of axonal injury.

A novel in vitro model of axonal injury using PC12 cells was designed to introduce traumatic alterations on neuronal processes and to identify mechanisms responsible for the formation of focal swellings by observation with phase-contrast and transmission electron microscopes. The injury on the processes was developed by one-dimensional, horizontal oscillation. Phase-contrast microscopic observation on the injured processes showed their terminal increase in diameter. Long term observation of cellular responses to the mechanical insult disclosed that the terminal swelling coincided with the detachment of growth cones from the culture plate. The finding suggests that the detachment of the growth cone would destroy a cytoskeletal network, which determines and maintains the cell shapes, and then cause the spherical deformation of the processes. Ultramicroscopically, the processes with terminal swellings regenerated the growth cones by the cytoskeletal reconstruction.

Animals↗
PubMed2001

N-Acetylaspartate reduction as a measure of injury severity and mitochondrial dysfunction following diffuse traumatic brain injury.

N-Acetylaspartate (NAA) is considered a neuron-specific metabolite and its reduction a marker of neuronal loss. The objective of this study was to evaluate the time course of NAA changes in varying grades of traumatic brain injury (TBI), in concert with the disturbance of energy metabolites (ATP). Since NAA is synthesized by the mitochondria, it was hypothesized that changes in NAA would follow ATP. The impact acceleration model was used to produce three grades of TBI. Sprague-Dawley rats were divided into the following four groups: sham control (n = 12); moderate TBI (n = 36); severe TBI (n = 36); and severe TBI coupled with hypoxia-hypotension (n = 16). Animals were sacrificed at different time points ranging from 1 min to 120 h postinjury, and the brain was processed for high-performance liquid chromatography (HPLC) analysis of NAA and ATP. After moderate TBI, NAA reduced gradually by 35% at 6 h and 46% at 15 h, accompanied by a 57% and 45% reduction in ATP. A spontaneous recovery of NAA to 86% of baseline at 120 h was paralleled by a restoration in ATP. In severe TBI, NAA fell suddenly and did not recover, showing critical reduction (60%) at 48 h. ATP was reduced by 70% and also did not recover. Maximum NAA and ATP decrease occurred with secondary insult (80% and 90%, respectively, at 48 h). These data show that, at 48 h post diffuse TBI, reduction of NAA is graded according to the severity of insult. NAA recovers if the degree of injury is moderate and not accompanied by secondary insult. The highly similar time course and correlation between NAA and ATP supports the notion that NAA reduction is related to energetic impairment.

Adenosine Triphosphate↗
PubMed2001

Increased expression of neuronal glucose transporter 3 but not glial glucose transporter 1 following severe diffuse traumatic brain injury in rats.

Traumatic brain injury results in an increased brain energy demand that is associated with profound changes in brain glycolysis and energy metabolism. Increased glycolysis must be met by increasing glucose supply that, in brain, is primarily mediated by two members of the facilitative glucose transporter family, Glut1 and Glut3. Glut1 is expressed in endothelial cells of the blood-brain barrier (BBB) and also in glia, while Glut3 is the primary glucose transporter expressed in neurons. However, few studies have investigated the changes in glucose transporter expression following traumatic brain injury, and in particular, the neuronal and glial glucose transporter responses to injury. This study has therefore focussed on investigating the expression of the glial specific 45-kDa isoform of Glut1 and neuronal specific Glut3 following severe diffuse traumatic brain injury in rats. Following impact-acceleration injury, Glut3 expression was found to increase by at least 300% as early as 4 h after induction of injury and remained elevated for at least 48 h postinjury. The increase in Glut3 expression was clearly evident in both the cerebral cortex and cerebellum. In contrast, expression of the glial specific 45-kDa isoform of Glut1 did not significantly change in either the cerebral cortex or cerebellum following traumatic injury. We conclude that increased glucose uptake after traumatic brain injury is primarily accounted for by increased neuronal Glut 3 glucose transporter expression and that this increased expression after trauma is part of a neuronal stress response that may be involved in increasing neuronal glycolysis and associated energy metabolism to fuel repair processes.

Animals↗
PubMedDate not supplied

Inflammatory response associated with axonal injury to spinal motoneurons in newborn rats.

Axonal injury in peripheral nerve results in massive motoneuron loss during development. The purpose of this study was to examine the response of phagocytic populations (brain macrophages, BMOs, versus microglia) after different types of axonal lesions (distal axotomy or avulsion) in newborn rats. The morphology, spatial location and activation state of these inflammatory cells were observed. Following spinal root avulsion, BMOs were signaled rapidly and specifically to the location of dying motoneurons in the spinal cord. A large number of BMOs were observed around the avulsed motoneurons on the lesioned side of the spinal cord 1 day following the lesion. These BMOs were large, round, and intensely stained by both antibodies against ED1 and OX-42. The number of BMOs decreased by 3 days and disappeared by 5 days after injury. At the same time, reactive microglia appeared in the lesioned area and rapidly reached the peak level by the 5th day following avulsion. These reactive microglia were medium in size with retracted cellular processes and were also intensely stained by both ED1 and OX-42 antibodies. The number and staining intensity of reactive microglia declined sharply by day 7 after the lesion. In contrast, after distal axotomy only microglia but not BMOs were observed in the lesioned area. These microglial cells were small in size with long and fine-branched processes. They were ED1-negative but OX-42-positive.

Animals↗