RESUMEN
Diffuse axonal injury (DAI), one of the most common and devastating type of traumatic brain injury, is the result of the shear force on axons due to severe rotational acceleration and deceleration. Neurogranin (NRGN) is a postsynaptic protein secreted by excitatory neurons, and synaptic dysfunction can alter extracellular NRGN levels. In this study, we examined NRGN levels in serum and cerebrospinal fluid (CSF) after experimental DAI in terms of their diagnostic value. Experimental DAI was induced using the Marmarou technique in male Wistar albino rats. Serum and CSF NRGN levels of the sham group, onehour, sixhour, 24hour, and 72hour postDAI groups were measured by ELISA method. DAI was verified by staining with hematoxylineosin and ßamyloid precursor protein in the rat brain samples. While no histopathological and immunohistochemical changes were observed in the early hours of the postDAI groups, the staining of the ßAPP visibly increased over time, with positivity being most frequent and intense in the 72hour group. It was found that serum NRGN levels were significantly lower in the 6hour group than in the sham group. The serum NRGN levels in the 24hour group were significantly higher than those in the sham group. This study showed a dichotomy of postDAI serum NRGN levels in consecutive time periods. NRGN levels in CSF were higher in the onehour group than in the sham group and returned to baseline by 72 hours, although not significantly. Our study provides an impression of serum and CSF NRGN levels in a rat DAI model in consecutive time periods. Further studies are needed to understand the diagnostic value of NRGN.
Asunto(s)
Lesión Axonal Difusa , Neurogranina , Ratas , Masculino , Animales , Neurogranina/metabolismo , Ratas Wistar , Lesión Axonal Difusa/metabolismo , Lesión Axonal Difusa/patología , Neuronas/metabolismo , Axones/metabolismoRESUMEN
Traumatic brain injury (TBI) significantly contributes to death and disability worldwide. However, treatment options remain limited. Here, we focus on a specific pathology of TBI, diffuse axonal brain injury (DABI), which describes the process of the tearing of nerve fibers in the brain after blunt injury. Most protocols to study DABI do not incorporate a specific model for that type of pathology, limiting their ability to identify mechanisms and comorbidities of DABI. In this study, we developed a magnetic resonance imaging (MRI) protocol for DABI in a rat model using a 3-T clinical scanner. We compared the neuroimaging outcomes with histologic and neurologic assessments. In a sample size of 10 rats in the sham group and 10 rats in the DABI group, we established neurological severity scores before the intervention and at 48 h following DABI induction. After the neurological evaluation after DABI, all rats underwent MRI scans and were subsequently euthanized for histological evaluation. As expected, the neurological assessment showed a high sensitivity for DABI lesions indicated using the ß-APP marker. Surprisingly, however, we found that the MRI method had greater sensitivity in assessing DABI lesions compared to histological methods. Out of the five MRI parameters with pathological changes in the DABI model, we found significant changes compared to sham rats in three parameters, and, as shown using comparative tests with other models, MRI was the most sensitive parameter, being even more sensitive than histology. We anticipate that this DABI protocol will have a significant impact on future TBI and DABI studies, advancing research on treatments specifically targeted towards improving patient quality of life and long-term outcomes.
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Lesión Axonal Difusa , Modelos Animales de Enfermedad , Imagen por Resonancia Magnética , Animales , Imagen por Resonancia Magnética/métodos , Ratas , Masculino , Lesión Axonal Difusa/diagnóstico por imagen , Lesión Axonal Difusa/patología , Ratas Sprague-Dawley , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Lesiones Traumáticas del Encéfalo/diagnóstico por imagen , Lesiones Traumáticas del Encéfalo/patologíaRESUMEN
Diffuse axonal injury (DAI) is a critical pathological facet of traumatic brain injury (TBI). Oxidative stress plays a significant role in the progress of DAI. Annexin A1 (AnxA1) has been demonstrated to benefit from recovery of neurofunctional outcomes after TBI. However, whether AnxA1 exhibits neuronal protective function by modulating oxidative stress in DAI remains unknown. Expression of AnxA1 was evaluated via real-time PCR and western blotting in rat brainstem after DAI. The neurological effect of AnxA1 following DAI through quantification of modified neurologic severity score (mNSS) was compared between wild-type and AnxA1-knockout rats. Brain edema and neuronal apoptosis, as well as expression of oxidative factors and inflammatory cytokines, were analyzed between wild-type and AnxA1 deficiency rats after DAI. Furthermore, mNSS, oxidative and inflammatory cytokines were assayed after timely administration of recombinant AnxA1 for DAI rats. In the brainstem of DAI, the expression of AnxA1 remarkably increased. Ablation of AnxA1 increased the mNSS score and brain water content of rats after DAI. Neuron apoptosis in the brainstem after DAI was exaggerated by AnxA1 deficiency. In addition, AnxA1 deficiency significantly upregulated the level of oxidative and inflammatory factors in the brainstem of DAI rats. Moreover, mNSS decreased by AnxA1 treatment in rats following DAI. Expression of oxidative and inflammatory molecules in rat brainstem subjected to DAI inhibited by AnxA1 administration. AnxA1 exhibited neuronal protective function in the progression of DAI mainly dependent on suppressing oxidative stress and inflammation.
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Anexina A1 , Lesiones Traumáticas del Encéfalo , Lesión Axonal Difusa , Animales , Ratas , Anexina A1/genética , Anexina A1/metabolismo , Encéfalo/metabolismo , Lesiones Traumáticas del Encéfalo/metabolismo , Citocinas/metabolismo , Lesión Axonal Difusa/patología , Inflamación/metabolismoRESUMEN
INTRODUCTION: Diffuse axonal injury (DAI), with high mortality and morbidity both in children and adults, is one of the most severe pathological consequences of traumatic brain injury. Currently, clinical diagnosis, disease assessment, disability identification, and postmortem diagnosis of DAI is mainly limited by the absent of specific molecular biomarkers. AREAS COVERED: In this review, we first introduce the pathophysiology of DAI, summarized the reported biomarkers in previous animal and human studies, and then the molecular biomarkers such as ß-Amyloid precursor protein, neurofilaments, S-100ß, myelin basic protein, tau protein, neuron-specific enolase, Peripherin and Hemopexin for DAI diagnosis is summarized. Finally, we put forward valuable views on the future research direction of diagnostic biomarkers of DAI. EXPERT OPINION: In recent years, the advanced technology has ultimately changed the research of DAI, and the numbers of potential molecular biomarkers was introduced in related studies. We summarized the latest updated information in such studies to provide references for future research and explore the potential pathophysiological mechanism on diffuse axonal injury.
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Lesiones Traumáticas del Encéfalo , Lesión Axonal Difusa , Adulto , Animales , Niño , Humanos , Encéfalo/metabolismo , Lesión Axonal Difusa/diagnóstico , Lesión Axonal Difusa/metabolismo , Lesión Axonal Difusa/patología , Lesiones Traumáticas del Encéfalo/metabolismo , Biomarcadores/metabolismo , ProteómicaRESUMEN
Traumatic brain injury (TBI) is now recognized as an insult triggering a dynamic process of degeneration and regeneration potentially evolving for years with chronic traumatic encephalopathy (CTE) as one major complication. Neurons are at the center of the clinical manifestations, both in the acute and chronic phases. Yet, in the acute phase, conventional neuropathology detects abnormalities predominantly in the axons, if one excludes contusions and hypoxic ischemic changes. We report the finding of ballooned neurons, predominantly in the anterior cingulum, in three patients who sustained severe TBI and remained comatose until death, 2 ½ weeks to 2 ½ months after the traumatic impact. All three cases showed severe changes of traumatic diffuse axonal injury in line with acceleration/deceleration forces. The immunohistochemical profile of the ballooned neurons was like that described in neurodegenerative disorders like tauopathies which were used as controls. The presence of αB-crystallin positive ballooned neurons in the brain of patients who sustained severe craniocerebral trauma and remained comatose thereafter has never been reported. We postulate that the co-occurrence of diffuse axonal injury in the cerebral white matter and ballooned neurons in the cortex is mechanistically reminiscent of the phenomenon of chromatolysis. Experimental trauma models with neuronal chromatolytic features emphasized the presence of proximal axonal defects. In our three cases, proximal swellings were documented in the cortex and subcortical white matter. This limited retrospective report should trigger further studies in order to better establish, in recent/semi-recent TBI, the frequency of this neuronal finding and its relationship with the proximal axonal defects.
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Lesiones Traumáticas del Encéfalo , Lesión Axonal Difusa , Humanos , Coma/complicaciones , Coma/patología , Lesión Axonal Difusa/complicaciones , Lesión Axonal Difusa/patología , Estudios Retrospectivos , Lesiones Traumáticas del Encéfalo/patología , Encéfalo/patología , Neuronas/patología , Axones/patologíaRESUMEN
Traumatic axonal injury (TAI) accounts for a large proportion of the mortality of traumatic brain injury (TBI). The diagnosis of TAI is currently of limited use for medicolegal purposes. It is known that axons in TAI are diffusely damaged by secondary processes other than direct head injury. However, the physiopathological mechanism of TAI is still elusive. The present study used RGD peptide, an antagonist of the mechanotransduction protein integrin, to explore the role of integrin-transmitted mechanical signalling in the pathogenesis of rat TAI. The rats were subjected to a linearly accelerating load, and changes in beta-amyloid precursor protein (ß-APP) expression, skeleton ultrastructure, skeleton protein neurofilament light (NF-L), and α-tubulin in the brainstem were observed, indicating that RGD could relieve the severity of axonal injury in TAI rats. In addition, the expression of ß-integrin was stronger and centralized in the brainstem of the deceased died from TAI compared to other nonviolent causes. This study examined the pathophysiology and biomechanics of TAI and assessed the role of integrin in the injury of microtubules and neurofilaments in TAI. Thus, we propose that integrin-mediated cytoskeletal injury plays an important role in TAI and that integrin has the potential as a biomarker for TAI.
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Lesiones Encefálicas , Lesión Axonal Difusa , Ratas , Animales , Ratas Sprague-Dawley , Lesiones Encefálicas/patología , Mecanotransducción Celular , Inmunohistoquímica , Axones/metabolismo , Axones/patología , Biomarcadores/metabolismo , Lesión Axonal Difusa/etiología , Lesión Axonal Difusa/metabolismo , Lesión Axonal Difusa/patologíaRESUMEN
Diffuse axonal injury (DAI) is the most severe pathological feature of traumatic brain injury (TBI). However, how primary axonal injury is induced by transient mechanical impacts remains unknown, mainly due to the low temporal and spatial resolution of medical imaging approaches. Here we established an axon-on-a-chip (AoC) model for mimicking DAI and monitoring instant cellular responses. Integrating computational fluid dynamics and microfluidic techniques, DAI was induced by injecting a precisely controlled micro-flux in the transverse direction. The clear correlation between the flow speed of injecting flux and the severity of DAI was elucidated. We next used the AoC to investigate the instant intracellular responses underlying DAI and found that the dynamic formation of focal axonal swellings (FAS) accompanied by Ca2+ surge occurs during the flux. Surprisingly, periodic axonal cytoskeleton disruption also occurs rapidly after the flux. These instant injury responses are spatially restricted to the fluxed axon, not affecting the overall viability of the neuron in the acute stage. Compatible with high-resolution live microscopy, the AoC provides a versatile system to identify early mechanisms underlying DAI, offering a platform for screening effective treatments to alleviate TBI.
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Lesiones Traumáticas del Encéfalo , Lesiones Encefálicas , Lesión Axonal Difusa , Humanos , Lesión Axonal Difusa/complicaciones , Lesión Axonal Difusa/diagnóstico , Lesión Axonal Difusa/patología , Dispositivos Laboratorio en un Chip , Lesiones Encefálicas/complicaciones , Lesiones Encefálicas/patología , Axones/fisiología , Lesiones Traumáticas del Encéfalo/patologíaRESUMEN
OBJECTIVE: The paper aimed at exploring the correlation between CT findings of diffuse axonal injury and the expression of neuronal aquaporin in patients with craniocerebral injury. PATIENTS AND METHODS: 150 patients with diffuse axonal injury diagnosed by CT and 50 healthy physical examinators were selected as the study objects. According to the craniocerebral CT and GCS scale scores, the patients were divided into DAI light group, medium group, and heavy group. The general conditions of patients were observed and recorded, and the brain pathological morphology, craniocerebral edema and CT imaging results of the patients in each group were compared. Changes in serum and brain AQP-4 levels were detected by RT-PCR and Western blot, and the correlation between CT manifestations of DAI and the expression of neuronal aquaporin was investigated. RESULTS: The results of DAI's pathological morphology, cerebral edema and CT imaging showed that the brain tissue of each group of DAI had a certain degree of injury. With the increase of the injury degree, the degree of edema and the number of axonal injuries sharply increased, and the difference was significant (p-value < 0.05). Therefore, CT could be used as an effective basis for the rapid and efficient diagnosis of DAI. RT-PCR, Western blot and Spearman correlation analysis showed that the levels of AQP-4 in the serum and brain tissue of DAI patients were significantly increased. With the increase of the degree of diffuse axonal injury, the expression level of AQP-4 was further increased, and the difference was significant (p-value < 0. 05). The CT manifestations of patients in each group were positively correlated with the expression level of AQP-4 protein. CONCLUSIONS: AQP-4 can be used as an important molecular index to judge the condition and prognosis of DAI, providing a new non-invasive detection method for the clinical diagnosis and treatment of DAI, which has high clinical application value.
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Acuaporinas , Traumatismos Craneocerebrales , Lesión Axonal Difusa , Acuaporinas/genética , Encéfalo/patología , Traumatismos Craneocerebrales/diagnóstico , Lesión Axonal Difusa/diagnóstico por imagen , Lesión Axonal Difusa/patología , Humanos , Tomografía Computarizada por Rayos XRESUMEN
Pathological outcomes of traumatic brain injury (TBI), including diffuse axonal injury, are influenced by the direction, magnitude, and duration of head acceleration during the injury exposure. Ovine models have been used to study injury mechanics and pathological outcomes of TBI. To accurately describe the kinematics of the head during an injury exposure, and better facilitate comparison with human head kinematics, anatomical coordinate systems (ACS) with an origin at the head or brain center of mass (CoM), and axes that align with the ovine Frankfort plane equivalent, are required. The aim of this study was to determine the mass properties of the sheep head and brain, and define an ACSvirtual for the head and brain, using anatomical landmarks on the skull with the aforementioned origins and orientation. Three-dimensional models of 10 merino sheep heads were constructed from computed tomography images, and the coordinates of the head and brain CoMs, relative to a previously reported sheep head coordinate system (ACSphysical ), were determined using the Hounsfield unit-mass density relationship. The ACSphysical origin was 34.8 ± 3.1 mm posterosuperior of the head CoM and 43.7 ± 1.7 anteroinferior of the brain CoM. Prominent internal anatomical landmarks were then used to define a new ACS (ACSvirtual ) with axes aligned with the Frankfort plane equivalent and an origin 10.4 ± 3.2 mm from the head CoM. The CoM and ACSvirtual defined in this study will increase the potential for comparison of head kinematics between ovine models and humans, in the context of TBI.
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Lesiones Traumáticas del Encéfalo , Lesión Axonal Difusa , Aceleración , Animales , Fenómenos Biomecánicos , Encéfalo/patología , Lesiones Traumáticas del Encéfalo/diagnóstico por imagen , Lesión Axonal Difusa/patología , Cabeza , OvinosRESUMEN
Studies show conflicting results regarding the prognostic significance of traumatic axonal injuries (TAI) in patients with traumatic brain injury (TBI). Therefore, we documented the presence of TAI in several brain regions, using different magnetic resonance imaging (MRI) sequences, and assessed their association to patient outcomes using machine learning. Further, we created a novel MRI-based TAI grading system with the goal of improving outcome prediction in TBI. We subsequently evaluated the performance of several TAI grading systems. We used a genetic algorithm to identify TAI that distinguish favorable from unfavorable outcomes. We assessed the discriminatory performance (area under the curve [AUC]) and goodness-of-fit (Nagelkerke pseudo-R2) of the novel Stockholm MRI grading system and the TAI grading systems of Adams and associates, Firsching and coworkers. and Abu Hamdeh and colleagues, using both univariate and multi-variate logistic regression. The dichotomized Glasgow Outcome Scale was considered the primary outcome. We examined the MRI scans of 351 critically ill patients with TBI. The TAI in several brain regions, such as the midbrain tegmentum, were strongly associated with unfavorable outcomes. The Stockholm MRI grading system exhibited the highest AUC (0.72 vs. 0.68-0.69) and Nagelkerke pseudo-R2 (0.21 vs. 0.14-0.15) values of all TAI grading systems. These differences in model performance, however, were not statistically significant (DeLong test, p > 0.05). Further, all included TAI grading systems improved outcome prediction relative to established outcome predictors of TBI, such as the Glasgow Coma Scale (likelihood-ratio test, p < 0.001). Our findings suggest that the detection of TAI using MRI is a valuable addition to prognostication in TBI.
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Lesiones Traumáticas del Encéfalo , Lesión Axonal Difusa , Lesiones Traumáticas del Encéfalo/diagnóstico por imagen , Enfermedad Crítica , Lesión Axonal Difusa/diagnóstico por imagen , Lesión Axonal Difusa/patología , Escala de Consecuencias de Glasgow , Humanos , Imagen por Resonancia Magnética , PronósticoRESUMEN
Finite element (FE) models of the human head are valuable instruments to explore the mechanobiological pathway from external loading, localized brain response, and resultant injury risks. The injury predictability of these models depends on the use of effective criteria as injury predictors. The FE-derived normal deformation along white matter (WM) fiber tracts (i.e., tract-oriented strain) recently has been suggested as an appropriate predictor for axonal injury. However, the tract-oriented strain only represents a partial depiction of the WM fiber tract deformation. A comprehensive delineation of tract-related deformation may improve the injury predictability of the FE head model by delivering new tract-related criteria as injury predictors. Thus, the present study performed a theoretical strain analysis to comprehensively characterize the WM fiber tract deformation by relating the strain tensor of the WM element to its embedded fiber tract. Three new tract-related strains with exact analytical solutions were proposed, measuring the normal deformation perpendicular to the fiber tracts (i.e., tract-perpendicular strain), and shear deformation along and perpendicular to the fiber tracts (i.e., axial-shear strain and lateral-shear strain, respectively). The injury predictability of these three newly proposed strain peaks along with the previously used tract-oriented strain peak and maximum principal strain (MPS) were evaluated by simulating 151 impacts with known outcome (concussion or non-concussion). The results preliminarily showed that four tract-related strain peaks exhibited superior performance than MPS in discriminating concussion and non-concussion cases. This study presents a comprehensive quantification of WM tract-related deformation and advocates the use of orientation-dependent strains as criteria for injury prediction, which may ultimately contribute to an advanced mechanobiological understanding and enhanced computational predictability of brain injury.
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Lesiones Traumáticas del Encéfalo , Modelos Teóricos , Fibras Nerviosas Mielínicas/patología , Sustancia Blanca/patología , Conmoción Encefálica/diagnóstico , Conmoción Encefálica/patología , Lesiones Traumáticas del Encéfalo/diagnóstico , Lesiones Traumáticas del Encéfalo/patología , Lesión Axonal Difusa/diagnóstico , Lesión Axonal Difusa/patología , HumanosRESUMEN
Traumatic brain injury (TBI) is a condition burdened by an extremely high rate of morbidity and mortality and can result in an overall disability rate as high as 50% in affected individuals. Therefore, the importance of identifying clinical prognostic factors for diffuse axonal injury (DAI) in (TBI) is commonly recognized as critical. The aim of the present review paper is to evaluate the most recent contributions from the relevant literature in order to understand how each single prognostic factor determinates the severity of the clinical syndrome associated with DAI. The main clinical factors with an important impact on prognosis in case of DAI are glycemia, early GCS, the peripheral oxygen saturation, blood pressure, and time to recover consciousness. In addition, the severity of the lesion, classified on the ground of the cerebral anatomical structures involved after the trauma, has a strong correlation with survival after DAI. In conclusion, modern findings concerning the role of reactive oxygen species (ROS) and oxidative stress in DAI suggest that biomarkers such as GFAP, pNF-H, NF-L, microtubule associated protein tau, Aß42, S-100ß, NSE, AQP4, Drp-1, and NCX represent a possible critical target for future pharmaceutical treatments to prevent the damages caused by DAI.
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Biomarcadores/metabolismo , Lesiones Traumáticas del Encéfalo/complicaciones , Lesión Axonal Difusa/patología , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismo , Lesión Axonal Difusa/etiología , Lesión Axonal Difusa/metabolismo , Humanos , PronósticoRESUMEN
Over 2.8 million people experience mild traumatic brain injury (TBI) in the United States each year, which may lead to long-term neurological dysfunction. The mechanical forces that are caused by TBI propagate through the brain to produce diffuse axonal injury (DAI) and trigger secondary neuroinflammatory cascades. The cascades may persist from acute to chronic time points after injury, altering the homeostasis of the brain. However, the relationship between the hallmark axonal pathology of diffuse TBI and potential changes in glial cell activation or morphology have not been established in a clinically relevant large animal model at chronic time points. In this study, we assessed the tissue from pigs subjected to rapid head rotation in the coronal plane to generate mild TBI. Neuropathological assessments for axonal pathology, microglial morphological changes, and astrocyte reactivity were conducted in specimens out to 1-year post-injury. We detected an increase in overall amyloid precursor protein pathology, as well as periventricular white matter and fimbria/fornix pathology after a single mild TBI. We did not detect the changes in corpus callosum integrity or astrocyte reactivity. However, detailed microglial skeletal analysis revealed changes in morphology, most notably increases in the number of microglial branches, junctions, and endpoints. These subtle changes were most evident in periventricular white matter and certain hippocampal subfields, and were observed out to 1-year post-injury in some cases. These ongoing morphological alterations suggest persistent change in neuroimmune homeostasis. Additional studies are needed to characterize the underlying molecular and neurophysiological alterations, as well as potential contributions to neurological deficits.
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Conmoción Encefálica/patología , Encéfalo/patología , Lesión Axonal Difusa/patología , Microglía/patología , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Axones/patología , Conmoción Encefálica/complicaciones , Modelos Animales de Enfermedad , Masculino , PorcinosRESUMEN
Axonal injury is a major contributor to the clinical symptomatology in patients with traumatic brain injury. Conventional neuroradiological tools, such as CT and MRI, are insensitive to diffuse axonal injury (DAI) caused by trauma. Diffusion tensor MRI parameters may change in DAI lesions; however, the nature of these changes is inconsistent. Multidimensional MRI is an emerging approach that combines T1, T2, and diffusion, and replaces voxel-averaged values with distributions, which allows selective isolation of specific potential abnormal components. By performing a combined post-mortem multidimensional MRI and histopathology study, we aimed to investigate T1-T2-diffusion changes linked to DAI and to define their histopathological correlates. Corpora callosa derived from eight subjects who had sustained traumatic brain injury, and three control brain donors underwent post-mortem ex vivo MRI at 7 T. Multidimensional, diffusion tensor, and quantitative T1 and T2 MRI data were acquired and processed. Following MRI acquisition, slices from the same tissue were tested for amyloid precursor protein (APP) immunoreactivity to define DAI severity. A robust image co-registration method was applied to accurately match MRI-derived parameters and histopathology, after which 12 regions of interest per tissue block were selected based on APP density, but blind to MRI. We identified abnormal multidimensional T1-T2, diffusion-T2, and diffusion-T1 components that are strongly associated with DAI and used them to generate axonal injury images. We found that compared to control white matter, mild and severe DAI lesions contained significantly larger abnormal T1-T2 component (P = 0.005 and P < 0.001, respectively), and significantly larger abnormal diffusion-T2 component (P = 0.005 and P < 0.001, respectively). Furthermore, within patients with traumatic brain injury the multidimensional MRI biomarkers differentiated normal-appearing white matter from mild and severe DAI lesions, with significantly larger abnormal T1-T2 and diffusion-T2 components (P = 0.003 and P < 0.001, respectively, for T1-T2; P = 0.022 and P < 0.001, respectively, for diffusion-T2). Conversely, none of the conventional quantitative MRI parameters were able to differentiate lesions and normal-appearing white matter. Lastly, we found that the abnormal T1-T2, diffusion-T1, and diffusion-T2 components and their axonal damage images were strongly correlated with quantitative APP staining (r = 0.876, P < 0.001; r = 0.727, P < 0.001; and r = 0.743, P < 0.001, respectively), while producing negligible intensities in grey matter and in normal-appearing white matter. These results suggest that multidimensional MRI may provide non-invasive biomarkers for detection of DAI, which is the pathological substrate for neurological disorders ranging from concussion to severe traumatic brain injury.
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Encéfalo/diagnóstico por imagen , Encéfalo/patología , Lesión Axonal Difusa/diagnóstico por imagen , Lesión Axonal Difusa/patología , Neuroimagen/métodos , Adulto , Anciano , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana EdadRESUMEN
The degree of brain injury is the governing factor for the magnitude of the patient's psycho- and physiological deficits post-injury, and the associated long-term consequences. The present scaling method used to segregate the patients among mild, moderate and severe phases of traumatic brain injury (TBI) has major limitations; however, a more continuous stratification of TBI is still elusive. With the anticipation that differentiating molecular markers could be the backbone of a robust method to triage TBI, we used a modified closed-head injury (CHI) Marmarou model with two impact heights (IH). By definition, IH directly correlates with the impact force causing TBI. In our modified CHI model, the rat skull was fitted with a helmet to permit a diffuse axonal injury. With the frontal cortex as the focal point of injury, the adjacent brain regions (hippocampus, HC and cerebellum, CB) were susceptible to diffuse secondary shock injury. At 8 days post injury (po.i.), rats impacted by 120 cm IH (IH120) took a longer time to find an escape route in the Barnes maze as compared to those impacted by 100 cm IH (IH100). Using a time-resolved interrogation of the transcriptomic landscape of HC and CB tissues, we mined those genes that altered their regulations in correlation with the variable IHs. At 14 days po.i., when all rats demonstrated nearly normal visuomotor performance, the bio-functional analysis suggested an advanced healing mechanism in the HC of IH100 group. In contrast, the HC of IH120 group displayed a delayed healing with evidence of active cell death networks. Combining whole genome rat microarrays with behavioral analysis provided the insight of neuroprotective signals that could be the foundation of the next generation triage for TBI patients.
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Lesiones Traumáticas del Encéfalo/genética , Lesiones Traumáticas del Encéfalo/patología , Cerebelo/patología , Hipocampo/patología , Transcriptoma , Animales , Peso Corporal , Lesiones Traumáticas del Encéfalo/psicología , Corticosterona/sangre , Lesión Axonal Difusa/genética , Lesión Axonal Difusa/patología , Lóbulo Frontal/lesiones , Traumatismos Cerrados de la Cabeza/genética , Traumatismos Cerrados de la Cabeza/patología , Masculino , Aprendizaje por Laberinto , Análisis por Micromatrices , Desempeño Psicomotor , Ratas , Ratas Wistar , Recuperación de la FunciónRESUMEN
INTRODUCTION: Traumatic axonal injury (TAI) is a condition defined as multiple, scattered, small hemorrhagic, and/or non-hemorrhagic lesions, alongside brain swelling, in a more confined white matter distribution on imaging studies, together with impaired axoplasmic transport, axonal swelling, and disconnection after traumatic brain injury (TBI). Ever since its description in the 1980s and the grading system by Adams et al., our understanding of the processes behind this entity has increased. METHODS: We performed a scoping systematic, narrative review by interrogating Ovid MEDLINE, Embase, and Google Scholar on the pathophysiology, biomarkers, and diagnostic tools of TAI patients until July 2020. RESULTS: We underline the misuse of the Adams classification on MRI without proper validation studies, and highlight the hiatus in the scientific literature and areas needing more research. In the past, the theory behind the pathophysiology relied on the inertial force exerted on the brain matter after severe TBI inducing a primary axotomy. This theory has now been partially abandoned in favor of a more refined theory involving biochemical processes such as protein cleavage and DNA breakdown, ultimately leading to an inflammation cascade and cell apoptosis, a process now described as secondary axotomy. CONCLUSION: The difference in TAI definitions makes the comparison of studies that report outcomes, treatments, and prognostic factors a daunting task. An even more difficult task is isolating the outcomes of isolated TAI from the outcomes of severe TBI in general. Targeted bench-to-bedside studies are required in order to uncover further pathways involved in the pathophysiology of TAI and, ideally, new treatments.
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Lesiones Traumáticas del Encéfalo/patología , Lesión Axonal Difusa/patología , Lesiones Traumáticas del Encéfalo/diagnóstico por imagen , Lesión Axonal Difusa/diagnóstico por imagen , Humanos , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patologíaRESUMEN
Traumatic brain injury is associated with elevated rates of neurodegenerative diseases such as Alzheimer's disease and chronic traumatic encephalopathy. In experimental models, diffuse axonal injury triggers post-traumatic neurodegeneration, with axonal damage leading to Wallerian degeneration and toxic proteinopathies of amyloid and hyperphosphorylated tau. However, in humans the link between diffuse axonal injury and subsequent neurodegeneration has yet to be established. Here we test the hypothesis that the severity and location of diffuse axonal injury predicts the degree of progressive post-traumatic neurodegeneration. We investigated longitudinal changes in 55 patients in the chronic phase after moderate-severe traumatic brain injury and 19 healthy control subjects. Fractional anisotropy was calculated from diffusion tensor imaging as a measure of diffuse axonal injury. Jacobian determinant atrophy rates were calculated from serial volumetric T1 scans as a measure of measure post-traumatic neurodegeneration. We explored a range of potential predictors of longitudinal post-traumatic neurodegeneration and compared the variance in brain atrophy that they explained. Patients showed widespread evidence of diffuse axonal injury, with reductions of fractional anisotropy at baseline and follow-up in large parts of the white matter. No significant changes in fractional anisotropy over time were observed. In contrast, abnormally high rates of brain atrophy were seen in both the grey and white matter. The location and extent of diffuse axonal injury predicted the degree of brain atrophy: fractional anisotropy predicted progressive atrophy in both whole-brain and voxelwise analyses. The strongest relationships were seen in central white matter tracts, including the body of the corpus callosum, which are most commonly affected by diffuse axonal injury. Diffuse axonal injury predicted substantially more variability in white matter atrophy than other putative clinical or imaging measures, including baseline brain volume, age, clinical measures of injury severity and microbleeds (>50% for fractional anisotropy versus <5% for other measures). Grey matter atrophy was not predicted by diffuse axonal injury at baseline. In summary, diffusion MRI measures of diffuse axonal injury are a strong predictor of post-traumatic neurodegeneration. This supports a causal link between axonal injury and the progressive neurodegeneration that is commonly seen after moderate/severe traumatic brain injury but has been of uncertain aetiology. The assessment of diffuse axonal injury with diffusion MRI is likely to improve prognostic accuracy and help identify those at greatest neurodegenerative risk for inclusion in clinical treatment trials.
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Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/patología , Lesión Axonal Difusa/patología , Enfermedades Neurodegenerativas/etiología , Enfermedades Neurodegenerativas/patología , Adulto , Anisotropía , Atrofia , Lesiones Traumáticas del Encéfalo/diagnóstico por imagen , Cuerpo Calloso/diagnóstico por imagen , Cuerpo Calloso/patología , Lesión Axonal Difusa/diagnóstico por imagen , Imagen de Difusión Tensora , Femenino , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/patología , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Enfermedades Neurodegenerativas/diagnóstico por imagen , Pruebas Neuropsicológicas , Valor Predictivo de las Pruebas , Desempeño Psicomotor , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Adulto JovenRESUMEN
A 17-year-old prisoner was found unconscious during a morning check. The previous night, he had been struck on the chin multiple times by one of the other inmates. The patient remained unconscious and eventually died after nearly 1.5 months of care. The primary task of the forensic pathological examination was to investigate the events leading to his death; therefore, it was necessary to examine whether there was a connection between the abuse and eventual death. In our case, the key element was the repetitive, mild-to-moderate force in abuse, resulting in grade I traumatic diffuse axonal damage. Due to progressive brain edema, aspiration subsequently developed, which eventually resulted in irreversible hypoxic damage of the brain.
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Lesión Axonal Difusa/patología , Abuso Físico , Adolescente , Encéfalo/patología , Hematoma Subdural/patología , Humanos , Masculino , Necrosis , PrisionerosRESUMEN
Blood-brain barrier (BBB) disruption exacerbates diffuse axonal injury (DAI), but the underlying mechanisms are not fully understood. Inactivation or deletion of erythropoietin-producing hepatoma (EPH) receptor A2 (EphA2) attenuated BBB damage and promoted tight junction formation. In this study, we aimed to investigate the role of EphA2 in the protection of BBB integrity and the relevant mechanisms involved in a rat model of DAI. Blocking activation of the EphA receptor by EphA2-Fc ameliorated axonal injury, cell apoptosis, and glial activation, protected BBB integrity and increased expression of the tight junction-associated proteins ZO-1, claudin-5 and occludin-1. In vitro BBB models established by human brain microvascular endothelial cells (HBMECs) were subjected to oxygen deprivation (OGD). Treatment with EphrinA1, which activates EphA2, exacerbated the OGD-induced destruction of permeability and integrity of the BBB models by reducing the expression of tight junction-associated proteins. However, inhibition of Rho-associated coiled coil-containing protein kinases 1 and 2 (ROCK1 and 2) abrogated all of the effects of EphrinA1 on the BBB models in vitro. In conclusion, we provide evidence that EphA2 plays an important role in the destruction of BBB integrity by decreasing the expression of tight junction proteins through the ROCK pathway.