Diffuse axonal injury after traumatic cerebral microbleeds: an evaluation of imaging techniques

Previous neuropathological studies regarding traumatic brain injury have primarily focused on changes in large structures, for example, the clinical prognosis after cerebral contusion, intrace- rebral hematoma, and epidural and subdural hematoma. In fact, many smaller injuries can also lead to severe neurological disorders. For example, cerebral microbleeds result in the dysfunc- tion of adjacent neurons and the disassociation between cortex and subcortical structures. These tiny changes cannot be adequately visualized on CT or conventional MRI. In contrast, gradient echo sequence-based susceptibility-weighted imaging is very sensitive to blood metabolites and microbleeds, and can be used to evaluate traumatic cerebral microbleeds with high sensitivity and accuracy. Cerebral microbleed can be considered as an important imaging marker for dif- fuse axonal injury with potential relevance for prognosis. For this reason, based on experimental and clinical studies, this study reviews the role of imaging data showing traumatic cerebral microbleeds in the evaluation of cerebral neuronal injury and neurofunctional loss.

The occurrence of diffuse axonal injury in the brain:associated with the accumulation and clearance of myelin debris

The accumulation of myelin debris may be a major contributor to the inlfammatory response after diffuse axonal injury. In this study, we examined the accumulation and clearance of myelin debris in a rat model of diffuse axonal injury. Oil Red O staining was performed on sections from the cerebral cortex, hippocampus and brain stem to identify the myelin debris. Seven days after diffuse axonal injury, many Oil Red O-stained particles were observed in the cerebral cortex, hippocampus and brain stem. In the cerebral cortex and hippocampus, the amount of myelin debris peaked at 14 days after injury, and decreased signiifcantly at 28 days. In the brain stem, the amount of myelin debris peaked at 7 days after injury, and decreased signiifcantly at 14 and 28 days. In the cortex and hippocampus, some myelin debris could still be observed at 28 days after diffuse axonal injury. Our ifndings suggest that myelin debris may persist in the rat central ner-vous system after diffuse axonal injury, which would hinder recovery.

Mild hypothermia for treatment of diffuse axonal injury: a quantitative analysis of diffusion tensor imaging

Fractional anisotropy values in diffusion tensor imaging can quantitatively reflect the consistency of nerve fibers after brain damage, where higher values generally indicate less damage to nerve fibers. Therefore, we hypothesized that diffusion tensor imaging could be used to evaluate the effect of mild hypothermia on diffuse axona[ injury. A total of 102 patients with diffuse axonal injury were randomly divided into two groups： normothermic and mild hypothermic treatment groups. Patient＇s modified Rankin scale scores 2 months after mild hypothermia were significant- ly lower than those for the normothermia group. The difference in average fractional anisotropy value for each region of interest before and after mild hypothermia was 1.32-1.36 times higher than the value in the normothermia group. Quantitative assessment of diffusion tensor imaging indicates that mild hypothermia therapy may be beneficial for patients with diffuse axonal injury.

Prognosis in prolonged coma patients with diffuse axonal injury assessed by somatosensory evoked potential

A total of 43 prolonged coma patients with diffuse axonal injury received the somatosensory evoked potential examination one month after injury in the First Affiliated Hospital, School of Medicine, Zhejiang University in China. Somatosensory evoked potentials were graded as normal, abnormal or absent （grades I-III） according to N20 amplitude and central conduction time. The outcome in patients with grade III somatosensory evoked potential was in each case unfavorable. The prognostic accuracy of grade III somatosensory evoked potential for unfavorable and non-awakening outcome was 100% and 80%, respectively. The prognostic accuracy of grade I somatosensory evoked potential for favorable and wakening outcome was 86% and 100%, respectively. These results suggest that somatosensory evoked potential grade is closely correlated with coma severity and degree of recovery. Somatosensory evoked potential is a valuable diagnostic tool to assess prognosis in prolonged coma patients with diffuse axonal injury.

Evaluation of non-typical diffuse axonal injury by magnetic resonance techniques

Because diffuse axonal injury（DAI）lacks specific clinical manifestations,it is difficult to evaluate DAI using computer tomography or conventional magnetic resonance imaging（MRI）.This study investigated the value of magnetic resonance techniques using fluid-attenuated inversion recovery（FLAIR）and proton magnetic resonance spectroscopy（1HMRS）for diagnosing DAI.The corpus callosum and basal nuclei were analyzed using morphological and functional imaging.Similar to the DAI group,the non-typical DAI group exhibited similar lesion characteristics on FLAIR,as well as post-injury neurochemical and molecular changes in the corpus callosum,as detected by 1HMRS.However,there were differences in degree and severity of injury.Compared to conventional MRI,FLAIR significantly increased lesion detection.1HMRS determined biochemical metabolism changes in midline structures following DAI,which resulted in increased diagnosis of non-typical DAI,which displayed similar lesion distribution,morphology,and function as DAI.Thus,the experiment proved the value of FLAIR and 1HMRS in non-typical DAI.

Dynamic changes in cerebral microcirculation and hypoxia in the early stages of diffuse axonal injury

This study demonstrated that damage to the cerebral microvasculature, the formation of microthrombi and swelling of vascular endothelial cells occur early and peak 12 hours after injury in a rat model of diffuse axonal injury. Moreover, these pathological changes were most evident in the cerebral cortex. Cerebral microcirculatory dysfunction peaked later and had a shorter duration than axonal injury. In addition, the radioactive imaging agent, 99Tcm-4, 9-diaza-2, 3, 10, 10- tetramethyldodecan-2, 11 -dione dioxime, was used to visualize the dynamic changes that occur in tissue with cerebral hypoxia. The results demonstrated that cerebral hypoxia occurs at an early stage in diffuse axonal injury. Cerebral hypoxia was evident 12 hours after injury and declined slightly 24 hours after injury, but was significantly higher than in the control group. The pathological changes that underpin microcirculatory dysfunction did not occur at the same time as axonal injury, but did occur simultaneously with neuronal injury. Cerebral hypoxia plays a key role in promoting the secondary brain injury that occurs after diffuse axonal injury.

Diagnostic value of fluid attenuated inversion recovery versus T_2-weighted image in diffuse axonal injury

BACKGROUND：At present, the most common examination modality for diffuse axonal injury （DAI） is CT or MRI. However, both methods exhibit low sensitivity in the diagnosis of DAI lesions. OBJECTIVE： To investigate the value of fluid attenuated inversion recovery （FLAIR） in the clinical diagnosis of DAI, and to compare with T2-weighted images. DESIGN, TIME AND SETTING： This prospective study was based on imaging analysis, and was performed in the First Affiliated Hospital of Chongqing Medical University （Chongqing, China） between October 2002 and April 2004. PARTICIPANTS： Sixty-three patients with craniocerebral injury were admitted to the Department of Neurosurgery at the First Affiliated Hospital of Chongqing Medical University, including 50 males and 13 females. The patients were included in the experiment and were divided into DAI （n=24） and non-DAI （n=39） groups, according to the emergent CT findings and clinical manifestations. METHODS： Both groups underwent MR examinations, including axial and sagittal T1 weighted images （TR = 450 ms, TE = 8-9 ms）, T2-weighted images （TR = 3 600 ms, TE = 100 ms）, and FLAIR （TR = 10 000 ms, TI = 2 500 ms, TE = 40 ms）, 8-mm thick and 2-mm wide, using a GE Sigma MRI device. MAIN OUTCOME MEASURES： The DAI diagnostic rate and lesion-detecting rate of T2-weighted images and FLAIR were determined. RESULTS： All 63 patients were included in the final analysis. The DAI diagnosis rates of FLAIR and T2-weighted images were 88% （21/24） and 62% （15/24）, respectively, of which the difference was statistically significant （P 〈 0.05）. T2-weighted images and FLAIR detected lesions located in the gray matter-white matter junction in parasagittal areas, the corpus callosum, deep periventricular white matter, basal ganglia, internal capsule, hippocampus, cerebellum, and brain stem, with a detailed amount of 123 and 256, respectively. FLAIR was significantly greater than T2-weighted images （P 〈 0.01）. CONCLUSION： FLAIR is superior to T2-weighted images for improving the DAI diagnostic rate and lesion-detecting rate, as well as revealing the extent and severity of DAI.

Susceptibility weighted imaging in the evaluation of hemorrhagic diffuse axonal injury

Diffuse axonal injury（DAI）is axonal and small vessel injury produced by a sudden acceleration of the head by an external force,and is a major cause of death and severe disability（Paterakis et al.,2000）.Prognosis is poorer in patients with apparent hemorrhage than in those without（Paterakis et al.,2000）.Therefore,it is important to identify the presence and precise position of hemorrhagic foci for a more accurate diagnosis.CT and magnetic resonance imaging（MRI）have long been applied in the diagnosis of DAI, but they are not sensitive enough for the detection of small hemorrhagic foci, and cannot meet the requirements for early diagnosis. A major advance in MRI has been the development of susceptibility weighted imaging （SWI）, which has greatly increased the ability to detect small hemorrhagic foci after DAI （Ashwal et al., 2006）.

8-hydroxy-2-(di-n-propylamino)tetralin intervenes with neural cell apoptosis following diffuse axonal injury

Previous studies have reported a neuroprotective effect of 8-hydroxy-2-（di-n-propylamino）tetralin （8-OH-DPAT） against traumatic brain injury. In accordance with the Marmarou method, rat models of diffuse axonal injury were established. 8-OH-DPAT was intraperitoneally injected into model rats. 8-OH-DPAT treated rats maintained at constant temperature served as normal temperature controls TUNEL results revealed that neural cell swelling, brain tissue necrosis and cell apoptosis occurred around the injured tissue. Moreover, the number of Bax-, Bcl-2- and caspase-3-positive cells increased at 6 hours after diffuse axonal injury, and peaked at 24 hours. However, brain injury was attenuated, the number of apoptotic cells reduced, Bax and caspase-3 expression decreased, and Bcl-2 expression increased at 6, 12, 24, 72 and 168 hours after diffuse axonal injury in normal temperature control and in 8-OH-DPAT-intervention rats. The difference was most significant at 24 hours. All indices in 8-OH-DPAT-intervention rats were better than those in the constant temperature group. These results suggest that 8-OH-DPAT inhibits Bax and caspase-3 expression, increases Bcl-2 expression, and reduces neural cell apoptosis, resulting in neuroprotection against diffuse axonal injury. This effect is associated with a decrease in brain temperature.

The usefulness of diffusion tensor imaging in detection of diffuse axonal injury in a patient with head trauma

Diffuse axonal injury is the predominant mechanism of injuries in patients with traumatic brain injury. Neither conventional brain computed tomography nor magnetic resonance imaging has shown sufficient sensitivity in the diagnosis of diffuse axonal injury. In the current study, we attempted to demonstrate the usefulness of diffusion tensor imaging in the detection of lesion sites of diffuse axonal injury in a patient with head trauma who had been misdiagnosed as having a stroke. A 44-year-old man fell from a height of about 2 m. Brain magnetic resonance imaging （32 months after onset） showed leukomalactic lesions in the isthmus of the corpus callosum and the left temporal lobe. He presented with mild quadriparesis, intentional tremor of both hands, and trunkal ataxia. From diffusion tensor imaging results of 33 months after traumatic brain injury onset, we found diffuse axonal injury in the right corticospinal tract （centrum semiovale, pons）, both fomices （columns and crus）, and both inferior cerebellar peduncles （cerebellar portions）. We think that diffusion tensor imaging could be a useful tool in the detection of lesion sites of diffuse axonal injury in patients with head trauma.

Brain-derived neurotrophic factor gene transfection promotes neuronal repair and neurite regeneration after diffuse axonal injury

This study sought to assess the potential of brain-derived neurotrophic factor （BDNF） to promote neuronal repair and regeneration in rats with diffuse axonal injury, and to examine the accompanying neurobiological changes. BDNF gene transfection reduced the severity of the pathological changes associated with diffuse axonal injury in cortical neurons of the frontal lobe and increased neurofilament protein expression. These findings demonstrate that BDNF can effectively promote neuronal repair and neurite regeneration after diffuse axonal injury.

Rosiglitazone ameliorates diffuse axonal injury by reducing loss of tau and up-regulating caveolin-1 expression

Rosiglitazone up-regulates caveolin-1 levels and has neuroprotective effects in both chronic and acute brain injury. Therefore, we postulated that rosiglitazone may ameliorate diffuse axonal injury via its ability to up-regulate caveolin-1, inhibit expression of amyloid-beta precursor protein, and reduce the loss and abnormal phosphorylation of tau. In the present study, intraperitoneal injection of rosiglitazone significantly reduced the levels of amyloid-beta precursor protein and hyperphosphorylated tau（phosphorylated at Ser^（404）（p-tau（S^（404）））, and it increased the expression of total tau and caveolin-1 in the rat cortex. Our results show that rosiglitazone inhibits the expression of amyloid-beta precursor protein and lowers p-tau（S^（404）） levels, and it reduces the loss of total tau, possibly by up-regulating caveolin-1. These actions of rosiglitazone may underlie its neuroprotective effects in the treatment of diffuse axonal injury.

Hippocampal expression of apoptotic protease activating factor-1 following diffuse axonal injury under mild hypothermia

The influence of mild hypothermia on neural cell apoptosis remains poorly understood. Therefore, the present study established rat models of diffuse axonal injury （DAI） at 33℃. Morris water maze results demonstrated significantly better learning and memory functions in DAI rats with hypothermia compared with DAI rats with normothermia. Expression of apoptotic protease activating factor-1 in the hippocampal CA1 region was significantly lower in the DAI hypothermia group compared with the DAI normothermia group. Expression of apoptotic protease activating factor-1 positively correlated with latency, but negatively correlated with platform location times and time of swimming in the quadrant area. Results suggested that post-traumatic mild hypothermia in a rat model of DAI could provide cerebral protection by attenuating expression of apoptotic protease activating factor-1.

Oxidative Stress and Inflammatory Response in Early Stage of Diffuse Axonal Injury in Rats

Objective: To investigate the role of oxidative stress and immunoinflammatory reaction in early stage of diffuse axonal injury (DAI). Methods: 96 adult male SD rats were divided into 2 groups (n = 48 in each): sham group and DAI group. Rat diffuse axonal injury was induced by a rat instant lateral head rotation device, which was developed to let the rat head spin 90 degree at the moment to cause shearing injury. The modified neurological severity score (mNSS), histomorphology, PI staining, GFAP immunofluorescent staining, SOD activity, CAT activity, MDA content and western blotting (IL-6,IL-1, JNK and p-JNK) in parietal cortex were investigated at 6 h, 1 d and 3 d after DAI. Results: The neurological severity scores, GFAP positive cell, PI positive cells, MDA, IL-6, IL-1, JNK and p-JNK were significantly increased and the SOD and CAT activities were decreased after DAI. Conclusion: Oxidative stress and immunoinflammatory reaction played important roles in DAI pathophysiological process in acute phase.

Present status of studies on diffuse axonal injury

OBJECTIVE: To explain the present status of study on diffuse axonal injury, investigate its pathogenesis and pathophysiological changes, and suggest principles for the diagnosis and treatment. DATA SOURCES: Articles about diffuse axonal injury published in English from January 1994 to October 2006 were searched in Pubmed database using the of 'diffuse axonal injury, pathogenesis, therapy'. STUDY SELECTION: The collected articles were primarily screened to select those associated with diffuse axonal injury, the obviously irrelated articles were excluded, and the rest ones were retrieved manually, and the full-texts were searched. DATA EXTRACTION: Totally 98 articles were collected, 41 of them were involved, and the other 57 were excluded. DATA SYNTHESIS: Diffuse axonal injury is mainly caused by acceleratory or deceleratory injury, and its pathophysiological change is a progressive duration, local axonal injury finally develops to axonal breakage, mainly includes inactivation of natrium channel, intracellular Ca2+ overloading, activation of calcium protease, caspase, etc., and mitochondrial injury. At present, there is still lack of effective therapeutic methods for diffuse axonal injury, so we should actively explore more effective methods to relieve the pain of patients and improve their prognosis. CONCLUSION: At present, diffuse axonal injury has not attracted enough attentions in China, the mechanisms for its diagnosis and attack are still unclear, and the treatments are mainly aiming at the symptoms.

Neurofilament 68 protein levels decreased after diffuse axonal injury in rats

Objective The present study was to observe the pathological mechanism of DAI in rats by Westerm blot test of NF68. Methods Diffuse axonal injury (DAI) were induced by using a kind of rotating brain injury model in Sprague-Dawley (SD) rats. Eighteen SD rats were divided into 3 groups randomly. We employed immunoreactiveity measurements on Western blots to examine NF68 levels in cerebral white metter, hippocampal,corpus callosm and brain stem tissue taken at several intervals after injury (30 minutes, 24 and 72 hours). Results Sham injury had no effect on NF68 protein levels. However, injury was associated with a significant loss of NF68, restricted to the brain stem. NF68 loss was detectable as early as 30 minutes and lasted at leasr 72 hours after injury. An incresing in the presence of lower molecular weight NF68 immunopositive bands(31.0,42.7 and 52 Kda) was associated with the decreasing of NF68. Putative NF68 breakdown products’ increase significantly until 1 day after injury. Conclusion This NF68

Observation on the Clinical Effect of Different Pressures in Hyperbaric Oxygen Therapy on Patients with Diffuse Axonal Injury

Objective:To observe the efficacy and significance of hyperbaric oxygen at different pressures in the treatment of diffuse axonal injury(DAI).Methods:Sixty patients with DAI were randomly divided into 1.8 ATA group(30 cases)and 2.2 ATA group(30 cases).The routine treatment for each group was the same.The 1.8 ATA.group received hyperbaric oxygen therapy under 1.8 ATA on the basis of routine treatment,whereas the 2.2 ATA group received hyperbaric oxygen therapy under 2.2 ATA.on the basis of routine treatment.The therapy was given once a day over 3 consecutive courses,with each course having 10 sessions.The Glasgow Coma Scale(GCS)on day 10,day 20,and day 30 after treatment,as well as the Glasgow Outcome Scale(GOS)after 6 months were compared between the two groups.Results:The mean GCS on day 10,day 20,and day 30 after treatment,as well as the mean GOS after 6 months of treatment in the 2.2 ATA group were significantly higher than those in the 1.8 ATA group(p<0.05).Conclusion:For patients with dififtise axonal injury,hyperbaric oxygen therapy is more effective with 2.2 ATA.compared with 1.8 ATA.

The Effects of Ultra-early Hyperbaric Oxygen Intervention in the Treatment of Diffuse Axonal Injury

Objective:To investigate the efficacy and mechanism of ultra-early hyperbaric oxygen intervention in the treatment of diffuse axonal injury(DAI).Methods:Eighty-six patients with diffuse axonal injury were selected and then divided into an ultra-early hyperbaric oxygen treatment group and a conventional treatment group with 43 patients in each group.The Glasgow Coma Scale(GCS)on the 10h day(10d),20h day(20d),and 30h day(30d)after treatment and the Glasgow Outcome Score(GOS)6 months later were observed and compared between both the groups.Results:The average score of the GCS at 10d,20d,and 30d as welll as the GOS 6 months later in the ultra-early hyperbaric oxygen treatment group were higher than those in the conventional treatment group(P<0.05).Conclusion:Hyperbaric oxygen therapy is one of the unique and effective methods in clinical treatment especially for the treatment of DAI patients and it is worthy of promotion.

Diffusion tensor tractography characteristics of axonal injury in concussion/mild traumatic brain injury

The main advantage of diffusion tensor tractography is that it allows the entire neural tract to be evaluated.In addition,configurational analysis of reconstructed neural tracts can indicate abnormalities such as tearing,narrowing,or discontinuations,which have been used to identify axonal injury of neural tracts in concussion patients.This review focuses on the characteristic features of axonal injury in concussion or mild traumatic brain injury(m TBI)patients through the use of diffusion tensor tractography.Axonal injury in concussion(m TBI)patients is characterized by their occurrence in long neural tracts and multiple injuries,and these characteristics are common in patients with diffuse axonal injury and in concussion(m TBI)patients with axonal injury.However,the discontinuation of the corticospinal tract is mostly observed in diffuse axonal injury,and partial tearing and narrowing in the subcortical white matter are frequently observed in concussion(m TBI)patients with axonal injury.This difference appears to be attributed to the observation that axonal injury in concussion(m TBI)patients is the result of weaker forces than those producing diffuse axonal injuries.In addition,regarding the fornix,in diffuse axonal injury,discontinuation of the fornical crus has been frequently reported,but in concussion(m TBI)patients,many collateral branches form in the fornix in addition to these findings in many case studies.It is presumed that the impact on the brain in TBI is relatively weaker than that in diffuse axonal injury,and that the formation of collateral branches occurs during the fornix recovery process.Although the occurrence of axonal injury in multiple areas of the brain is an important feature of diffuse axonal injury,case studies in concussion(m TBI)have shown that axonal injury occurs in multiple neural tracts.Because axonal injury lesions in m TBI patients may persist for approximately 10 years after injury onset,the characteristics of axonal injury in concussion(m TBI)patients,which are reviewed and categorized in this review,are expected to serve as useful supplementary information in the diagnosis of axonal injury in concussion(m TBI)patients.

Diffusion tensor imaging as a tool to detect presymptomatic axonal degeneration in a preclinical spinal cord model of amyotrophic lateral sclerosis

The G93A-SOD1 mice model and MRI diffusion as a preclinical tool to study amyotrophic lateral sclerosis （ALS）： ALS is a progressive neurological disease characterized primarily by the development of limb paralysis, which eventually leads to lack of control on muscles under voluntary control and death within 3–5 years. Genetic heterogeneity and environmental factors play a critical role in the rate of disease progression and patients display faster declines once the symptoms have manifested. Since its original discovery, ALS has been associated with pathological alterations in motor neurons located in the spinal cord （SC）, where neuronal loss by a mutation in the protein superoxide dismutase in parenthesis （mSOD1） and impairment in axonal connectivity, have been linked to early functional impairments. In addition,mechanisms of neuroinflammation, apoptosis, necroptosis and autophagy have been also implicated in the development of this disease. Among different animal models developed to study ALS, the transgenic G93A-SOD1 mouse has become recognized as a benchmark model for preclinical screening of ALS therapies. Furthermore, the progressive alterations in the locomotor phenotype expressed in this model closely resemble the progressive lower limb dysfunction of ALS patients. Among other imaging tools, MR diffusion tensor imaging （DTI） has emerged as a crucial, noninvasive and real time neuroimaging tool to gather information in ALS. One of the current concerns with the use of DTI is the lack of biological validation of the microstructural information given by this technique. Although clinical studies using DTI can provide a remarkable insight on the targets of neurodegeneration and disease course,they lack histological correlations. To address these shortcomings, preclinical models can be designed to validate the microstructural information unveiled by this particular MRI technique. Thus, the scope of this review is to describe how MRI diffusion and optical microscopy evaluate axonal structural changes at early stages of the disease in a preclinical model of ALS.