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T K McIntosh

Publications and source records attributed to T K McIntosh.

At least 19 recordsLinked to original sources
PubMed1999

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

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

Adolescent↗
PubMed1999

Experimental investigation of cerebral contusion: histopathological and immunohistochemical evaluation of dynamic cortical deformation.

We used a new approach, termed dynamic cortical deformation (DCD), to study the neuronal, vascular, and glial responses that occur in focal cerebral contusions. DCD produces experimental contusion by rapidly deforming the cerebral cortex with a transient, nonablative vacuum pulse of short duration (25 milliseconds) to mimic the circumstances of traumatic injury. A neuropathological evaluation was performed on brain tissue from adult rats sacrificed 3 days following induction of either moderate (4 psi, n = 6) or high (8 psi, n = 6) severity DCD. In all animals, DCD produced focal hemorrhagic lesions at the vacuum site without overt damage to other regions. Examination of histological sections showed localized gross tissue and neuronal loss in the cortex at the injury site, with the volume of cell loss dependent upon the mechanical loading (p < 0.001). Axonal pathology shown with neurofilament immunostaining (SMI-31 and SMI-32) was observed in the subcortical white matter inferior to the injury site and in the ipsilateral internal capsule. No axonal injury was observed in the contralateral hemisphere or in any remote regions. Glial fibrillary acidic protein (GFAP) immunostaining revealed widespread reactive astrocytosis surrounding the necrotic region in the ipsilateral cortex. This analysis confirms that rapid mechanical deformation of the cortex induces focal contusions in the absence of primary damage to remote areas 3 days following injury. Although it is suggested that massive release of neurotoxic substances from a contusion may cause damage throughout the brain, these data emphasize the importance of combined injury mechanisms, e.g. mechanical distortion and excitatory amino acid mediated damage, that underlie the complex pathology patterns observed in traumatic brain injury.

Animals↗
PubMed1998

Experimental brain injury induces regionally distinct apoptosis during the acute and delayed post-traumatic period.

The temporal pattern of apoptosis in the adult rat brain after lateral fluid-percussion (FP) brain injury was characterized using terminal deoxynucleotidyl-transferase-mediated biotin-dUTP nick end labeling (TUNEL) histochemistry and agarose gel electrophoresis. Male Sprague Dawley rats were subjected to brain injury and killed for histological analysis at intervals from 12 hr to 2 months after injury (n = 3/time point). Sham (uninjured) controls were subjected to anesthesia with (n = 3) or without (n = 3) surgery. Apoptotic TUNEL-positive cells were defined using stringent morphological criteria including nuclear shrinkage and fragmentation and condensation of chromatin and cytoplasm. Double-labeled immunocytochemistry was performed to identify TUNEL-positive neurons (anti-neurofilament monoclonal antibody RM044), astrocytes (anti-glial fibrillary acidic protein polyclonal antibody), and oligodendrocytes (anti-cyclic nucleotide phosphohydrolase polyclonal antibody). Compared with that seen with sham controls, in the injured cortex, significant apoptosis occurred at 24 hr (65 +/- 19 cells; p < 0.05) with a second, more pronounced response at 1 week after injury (91 +/- 24 cells; p < 0.05). The number of apoptotic cells in the white matter was increased as early as 12 hr after injury and peaked by 1 week (33 +/- 6 cells; p < 0.05). An increase in apoptotic cells was observed in the hippocampus at 48 hr (13 +/- 8), whereas in the thalamus, the apoptotic response was delayed, peaking at 2 weeks after injury (151 +/- 71 cells; p < 0.05). By 2 months, the number of apoptotic cells in most regions had returned to uninjured levels. At 24 hr after injury, TUNEL-labeled neurons and oligodendrocytes were localized primarily to injured cortex. By 1 week after injury, populations of TUNEL-labeled astrocytes and oligodendrocytes were present in the injured cortex, while double-labeled neurons were present predominantly in injured cortex and thalamus, with a few scattered in the hippocampus. DNA agarose gels confirmed morphological identification of apoptosis. These data suggest that the apoptotic response to trauma is regionally distinct and may be involved in both acute and delayed patterns of cell death.

Analysis of Variance↗
PubMed1998

Effects of the NMDA antagonist CP-98,113 on regional cerebral edema and cardiovascular, cognitive, and neurobehavioral function following experimental brain injury in the rat.

The present study examined the effects of CP-98,113, an N-methyl-d-aspartate (NMDA) receptor blocker, on cardiovascular variables, neurobehavioral motor function, spatial memory deficits, and cerebral edema formation following lateral (parasagittal) fluid-percussion (FP) brain injury in the rat. In Study 1, we compared the cardiovascular effects of i.p. administration of CP-98, 113 at 15 min postinjury at doses of 1 mg/kg, 2 mg/kg, 5 mg/kg, or 20 mg/kg (n=8/dose). Animals receiving 1 mg/kg to 5 mg/kg CP-98,113 showed slight but nonsignificant decreases in blood pressure, while those receiving the highest dose (20 mg/kg) showed significant hypotension. Based upon those observations, the 5 mg/kg dose was chosen as the optimal dose for subsequent behavioral studies. In Study 2, 15 min following lateral FP brain injury of moderate severity (2.5 atm), animals randomly received either CP-98,113 (5 mg/kg, i.p., n=23) followed by a 24-h subcutaneous infusion (1.5 mg kg-1 h-1) by means of a miniature osmotic pump, or identical volume of vehicle (n=24), and were evaluated for neurologic motor function (n=11/drug vs. 11/vehicle), memory function, and cerebral edema (n=12/drug vs. 13/vehicle). CP-98,113 (5 mg/kg) significantly attenuated neurologic motor dysfunction at 24 h (p<0.01) and 2 weeks (p<0.05) postinjury, reduced posttraumatic impairment in spatial memory observed at 48 h postinjury (p<0.001), and significantly reduced focal brain edema in the cortex adjacent to the site of maximal injury at 48 h postinjury (injury penumbra) (p<0.001). These results suggest that blockade of the NMDA receptor may attenuate the deleterious sequelae of traumatic brain injury.

Animals↗
PubMed1998

Riluzole attenuates cortical lesion size, but not hippocampal neuronal loss, following traumatic brain injury in the rat.

The neuroprotective effects of Riluzole, a compound with several mechanisms of action including the inhibition of sodium channel activity and glutamate release, were evaluated in a rat model of parasagittal fluid-percussion (FP) brain injury. Male Sprague-Dawley rats (350-400 g, n = 17) were anesthetized with sodium pentobarbital (60 mg/kg i.p.) and subjected to parasagittal FP brain injury of moderate severity (2.3-2.5 atm). Fifteen min following injury, animals randomly received an i.v. bolus of either Riluzole (8 mg/kg, n = 8) or vehicle (n = 9), followed by subcutaneous injections (identical dose) at 6 hr and 24 hr. Two weeks after injury and drug treatment, animals were sacrificed and a series of brain sections, stained with Hematoxylin and Eosin (H&E) or cresyl violet, were evaluated for quantitative cortical lesion volume and cell counts of hippocampal CA3 neurons, respectively, using a computerized image analysis system. Administration of Riluzole significantly reduced FP-induced tissue loss in the temporal/occipital cortices ipsilateral to the site of impact by 46%, compared to vehicle-treated, brain-injured animals (P = 0.01). In contrast, the selective neuronal loss observed in the CA3 region of the ipsilateral hippocampus was unaffected by Riluzole treatment. The present study demonstrates that Riluzole can attenuate cortical lesion size following brain trauma. These neuroprotective effects may be related to the synergy of the different mechanisms of action of Riluzole.

Animals↗
PubMed1998

Twofold overexpression of human beta-amyloid precursor proteins in transgenic mice does not affect the neuromotor, cognitive, or neurodegenerative sequelae following experimental brain injury.

By using transgenic mice that overexpress human beta-amyloid precursor proteins (APPs) at levels twofold higher than endogenous APPs, following introduction of the human APP gene in a yeast artificial chromosome (YAC), we examined the effects of controlled cortical impact (CCI) brain injury on neuromotor/cognitive dysfunction and the development of Alzheimer's disease (AD)-like neuropathology. Neuropathological analyses included Nissl-staining and immunohistochemistry to detect APPs, beta-amyloid (Abeta), neurofilament proteins, and glial fibrillary acidic protein, whereas Abeta levels were measured in brain homogenates from mice subjected to CCI and control mice by using a sensitive sandwich enzyme-linked immunosorbent assay. Twenty APP-YAC transgenic mice and 17 wild type (WT) littermate controls were anesthetized and subjected to CCI (velocity, 5 m/second; deformation depth, 1 mm). Sham (anesthetized but uninjured) controls (n = 10 APP-YAC; n = 8 WT) also were studied. Motor function was evaluated by using rotarod, inclined-plane, and forelimb/hindlimb flexion tests. The Morris water maze was used to assess memory. Although CCI induced significant motor dysfunction and cognitive deficits, no differences were observed between brain-injured APP-YAC mice and WT mice at 24 hours and 1 week postinjury. By 1 week postinjury, both cortical and hippocampal CA3 neuron loss as well as extensive astrogliosis were observed in all injured animals, suggesting that overexpression of human APPs exhibited no neuroprotective effects. Although AD-like pathology (including amyloid plaques) was not observed in either sham or brain-inj ured animals, a significant decrease in brain concentrations of only Abeta terminating at amino acid 40 (Abeta x-40) was observed following brain injury in APP-YAC mice (P < 0.05 compared with sham control levels). Our data show that the APP-YAC mice do not develop AD-like neuropathology following traumatic brain injury. This may be because this injury does not induce elevated levels of the more amyloidogenic forms of human Abeta (i.e., Abeta x-42/43) in these mice.

Amyloid beta-Peptides↗
PubMed1998

Brain trauma induces massive hippocampal neuron death linked to a surge in beta-amyloid levels in mice overexpressing mutant amyloid precursor protein.

Although brain trauma is a risk factor for Alzheimer's disease, no experimental model has been generated to explore this relationship. We developed a model of brain trauma in transgenic mice that overexpress mutant human amyloid precursor protein (PDAPP) leading to the appearance of Alzheimer's disease-like beta-amyloid (Abeta) plaques beginning at 6 months of age. We induced cortical impact brain injury in the PDAPP animals and their wild-type littermates at 4 months of age, ie, before Abeta plaque formation, and evaluated changes in posttraumatic memory function, histopathology, and regional tissue levels of the Abeta peptides Abeta1-40 and Abeta1-42. We found that noninjured PDAPP mice had impaired memory function compared to noninjured wild-type littermates (P < 0.01) and that brain-injured PDAPP mice had more profound memory dysfunction than brain-injured wild-type littermates (P < 0.001). Although no augmentation of Abeta plaque formation was observed in brain-injured PDAPP mice, a substantial exacerbation of neuron death was found in the hippocampus (P < 0.001) in association with an acute threefold increase in Abeta1-40 and sevenfold increase in Abeta1-42 levels selectively in the hippocampus (P < 0.01). These data suggest a mechanistic link between brain trauma and Abeta levels and the death of neurons.

Amyloid beta-Peptides↗
PubMed1998

Enduring cognitive, neurobehavioral and histopathological changes persist for up to one year following severe experimental brain injury in rats.

Clinical studies have demonstrated that patients sustain prolonged behavioral deficits following traumatic brain injury, in some cases culminating in the cognitive and histopathological hallmarks of Alzheimer's disease. However, few studies have examined the long-term consequences of experimental traumatic brain injury. In the present study, anesthetized male Sprague-Dawley rats (n = 185) were subjected to severe lateral fluid-percussion brain injury (n = 115) or sham injury (n = 70) and evaluated up to one year post-injury for cognitive and neurological deficits and histopathological changes. Compared with sham-injured controls, brain-injured animals showed a spatial learning impairment that persisted up to one year post-injury. In addition, deficits in specific neurologic motor function tasks also persisted up to one year post-injury. Immunohistochemistry using multiple antibodies to the amyloid precursor protein and/or amyloid precursor protein-like proteins revealed novel axonal degeneration in the striatum, corpus callosum and injured cortex up to one year post-injury and in the thalamus up to six months post-injury. Histologic evaluation of injured brains demonstrated a progressive expansion of the cortical cavity, enlargement of the lateral ventricles, deformation of the hippocampus, and thalamic calcifications. Taken together, these findings indicate that experimental traumatic brain injury can cause long-term cognitive and neurologic motor dysfunction accompanied by continuing neurodegeneration.

Amyloid beta-Peptides↗
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

High-field proton magnetic resonance spectroscopy of a swine model for axonal injury.

A miniature swine model for diffuse brain injury has recently been developed that replicates the inertial loading conditions associated with rotational acceleration during automotive accidents. The swine model induces diffuse axonal pathology without macroscopic injury such as contusions and hematomas, thus affording a unique opportunity to study axonal injury with noninvasive techniques such as magnetic resonance imaging (MRI) and spectroscopy (MRS). In the present study, we evaluated this diffuse injury model with proton MRS, in vivo, using a high-field (4.0-T) MR scanner, since MRS has been demonstrated as a sensitive probe for detecting neurochemical abnormalities. Our study examined a region of the swine brain at timepoints before and after brain injury. Spectroscopic results indicate that N-acetylaspartate/creatine is diminished by at least 20% in regions of confirmed axonal pathology, whereas conventional MRI did not detect any abnormalities. These findings suggest that MRS has high sensitivity in diagnosing microscopic pathology following diffuse brain injury.

Animals↗
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

Increased jun immunoreactivity in an in vitro model of mammalian spinal neuron physical injury.

Dendrites were transected from murine spinal neurons. Unlesioned neurons showed dark nucleolar and patchy cytoplasmic jun immunostaining. By 0.5 and 2 h, most lesioned neurons stained intensely throughout the soma. However, at 24 h only dead neurons displayed intense somal staining, and 100% of the surviving cells stained like unlesioned controls. Correlation of immunostaining patterns with viability, injury, and death suggests jun gene expression may influence the survival of neurons after physical injury.

Animals↗
PubMed1998

Magnetic resonance spectroscopy of diffuse brain trauma in the pig.

The acute metabolic events linked to the evolution of selective axonal pathology in the white matter following diffuse brain injury have not previously been evaluated due to the paucity of relevant experimental models. Here, we utilized a new model of inertial brain injury in the pig that selectively damages axons in the white matter, and applied proton and phosphorous magnetic resonance spectroscopy (MRS) to noninvasively monitor the temporal course of metabolic changes following trauma. Evaluating four pigs with MRS prior to injury, within 1 h and 3 and 7 days postinjury, we found that widespread axonal injury was produced in the absence of changes in pH, PCr/Pi, or the concentrations of ATP, and lactate. However, we did observe an acute 60% loss of intracellular Mg2+ levels, which gradually resolved by 7 days postinjury. In addition, we found that the levels of the neuron marker, N-acetylaspartate (NAA), acutely dropped 20% and remained persistently decreased for at least 7 days postinjury. Moreover, the changes in Mg2+ and NAA were found with MRS in the absence of abnormalities with conventional magnetic resonance imaging (MRI). These results show that (1) profound alterations in intracellular metabolism occur acutely following diffuse axonal pathology in the white matter, but in the absence of indicators of ischemia, and (2) axonal pathology may be evaluated with high sensitivity utilizing noninvasive MRS techniques.

Adenosine Triphosphate↗
PubMed1998

Novel pharmacologic strategies in the treatment of experimental traumatic brain injury: 1998.

The mechanisms underlying secondary or delayed cell death following traumatic brain injury are poorly understood. Recent evidence from experimental models suggests that widespread neuronal loss is progressive and continues in selectively vulnerable brain regions for months to years after the initial insult. The mechanisms underlying delayed cell death are believed to result, in part, from the release or activation of endogenous "autodestructive" pathways induced by the traumatic injury. The development of sophisticated neurochemical, histopathological and molecular techniques to study animal models of TBI have enabled researchers to begin to explore the cellular and genomic pathways that mediate cell damage and death. This new knowledge has stimulated the development of novel therapeutic agents designed to modify gene expression, synthesis, release, receptor or functional activity of these pathological factors with subsequent attenuation of cellular damage and improvement in behavioral function. This article represents a compendium of recent studies suggesting that modification of post-traumatic neurochemical and cellular events with targeted pharmacotherapy can promote functional recovery following traumatic injury to the central nervous system.

Animals↗
PubMed1998

In vitro central nervous system models of mechanically induced trauma: a review.

Injury is one of the leading causes of death among all people below the age of 45 years. In the United States, traumatic brain injury (TBI) and spinal cord injury (SCI) together are responsible for an estimated 90,000 disabled persons annually. To improve treatment of the patient and thereby decrease the associated mortality, morbidity, and cost, several in vivo models of central nervous system (CNS) injury have been developed and characterized over the past two decades. To complement the ability of these in vivo models to reproduce the sequelae of human CNS injury, in vitro models of neuronal injury have also been developed. Despite the inherent simplifications of these in vitro systems, many aspects of the posttraumatic sequelae are faithfully reproduced in cultured cells, including ultrastructural changes, ionic derangements, alterations in electrophysiology, and free radical generation. This review presents a number of these in vitro systems, detailing the mechanical stimuli, the types of tissue injured, and the in vivo injury conditions most closely reproduced by the models. The data generated with these systems is then compared and contrasted with data from in vivo models of CNS injury. We believe that in vitro models of mechanical injury will continue to be a valuable tool to study the cellular consequences and evaluate the potential therapeutic strategies for the treatment of traumatic injury of the CNS.

Adult↗
PubMed1998

BCL-2 overexpression attenuates cortical cell loss after traumatic brain injury in transgenic mice.

The proto-oncogene, BCL-2, has been suggested to participate in cell survival during development of, and after injury to, the CNS. Transgenic (TG) mice overexpressing human Bcl-2 (n = 21) and their wild-type (WT) littermates (n = 18) were subjected to lateral controlled cortical impact brain injury. Lateral controlled cortical impact brain injury resulted in the formation of a contusion in the injured cortex at 2 days, which developed into a well-defined cavity by 7 days in both WT and TG mice. At 7 days after injury, brain-injured TG mice had a significantly reduced cortical lesion (volume = 1.99 mm3) compared with that of the injured WT mice (volume = 5.1 mm3, P < 0.01). In contrast, overexpression of BCL-2 did not affect the extent of hippocampal cell death after lateral controlled cortical impact brain injury. Analysis of motor function revealed that both brain-injured WT and TG mice exhibited significant right-sided deficits at 2 and 7 days after injury (P < 0.05 compared with the uninjured controls). Although composite neuroscores (sum of scores from forelimb and hind limb flexion, lateral pulsion, and inclined plane tests) were not different between WT and TG brain-injured mice, TG mice had a slightly but significantly reduced deficit in the inclined plane test (P < 0.05 compared to the WT mice). These data suggest that the cell death regulatory gene, BCL-2, may play a protective role in the pathophysiology of traumatic brain injury.

Animals↗
PubMed1998

Proton magnetic resonance spectroscopy for detection of axonal injury in the splenium of the corpus callosum of brain-injured patients.

OBJECT: This study was conducted to determine whether proton magnetic resonance spectroscopy (MRS) is a sensitive method for detecting diffuse axonal injury, which is a primary sequela of traumatic brain injury (TBI). Diffuse axonal injury is characterized by selective damage to white matter tracts that is caused in part by the severe inertial strain created by rotational acceleration and deceleration, which is often associated with motor vehicle accidents. This axonal injury is typically difficult to detect by using conventional imaging techniques because it is microscopic in nature. The splenium was selected because it is a site vulnerable to shearing forces that produce diffuse axonal injury. METHODS: The authors used proton MRS to evaluate the splenium, the posterior commissure of the corpus callosum, in normal control volunteers and in patients with TBI. Proton MRS provided an index of neuronal and axonal viability by measuring levels of N-acetyl aspartate (NAA). CONCLUSIONS: A majority of mildly brain injured patients, as well as those more severely injured, showed diminished NAA/creatine (Cr) levels in the splenium compared with normal control volunteers. The patients displaying lowered NAA/Cr in the splenium were also likely to exhibit lowered NAA/Cr in lobar white matter. Also, the levels of NAA/Cr in the splenium of normal volunteers were higher compared with those found in lobar white matter. Decreases in NAA/Cr levels in the splenium may be a marker for diffuse injury. A proton MRS examination may be particularly useful in evaluating mildly injured patients with unexplained neurological and cognitive deficits. It is concluded that MRS is a sensitive tool in detecting axonal injury.

Acceleration↗