Role of integrin and its potential as a novel postmortem biomarker in traumatic axonal injury.

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.

[Expert errors in formulating a forensic diagnosis and conclusions in cases of diffuse axonal brain damage]. / Ekspertnye oshibki pri formulirovanii sudebno-meditsinskogo diagnoza i vyvodov v sluchayakh diffuznogo aksonal'nogo povrezhdeniya mozga.

The study objective is to review expert errors in the wording of a post-mortem diagnosis and expert conclusions in cases of traumatic brain injury with diffuse axonal brain damage. We reviewed 50 corpse examinations of those who died from a traumatic brain injury with diffuse axonal brain damage. A retrospective analysis of the results of expert examinations, the structure of the post-mortem forensic diagnosis, and the validity of expert conclusions showed that expert errors were made in 30% of cases. In 93% of cases, the errors were epistemological due to the lack of a scientifically based methodological approach to the expert opinion on a particular mechanism for the development of traumatic brain injury with diffuse axonal brain damage; and lack of professional expertise. A case is provided demonstrating the most common expert errors in the examination of this type of traumatic brain injury.

[Clinical presentation and gross appearance of diffuse axonal injury in the early post-injury period]. / Klinicheskaya i makroskopicheskaya kharakteristika diffuznogo aksonal'nogo povrezhdeniya mozga v ostrom posttravmaticheskom periode.

The objective of the study was to investigate and characterize the clinical presentation, and establish macroscopic diagnostic signs of diffuse axonal injury (DAI) in the early (up to 3 days) post-injury period. In DAI, coma develops immediately after head injury and persists for 3 days post-injury until death. The coma is accompanied by dominant primary stem neurological symptoms, hemodynamic and respiratory disturbances and does not progress to a vegetative state. Lifetime computed tomography reveals cerebral hemorrhage in 40.5% of cases. We established the macroscopic signs of head injury in DAI. For the postmortem diagnosis of DAI, a detailed macroscopic appearance of pathognomonic cerebral hemorrhages is given, which are most frequently (67.5%) localized in the corpus callosum (CC), namely in the area from its genu to the middle of the trunk (97%). A rational, improved scheme of excision of CC trunk areas for the histological study is proposed.

[Problems of forensic diagnosis of diffuse axonal brain injury in the acute post-traumatic period]. / Problemy sudebno-meditsinskoi diagnostiki ostrogo perioda diffuznogo aksonal'nogo povrezhdeniya golovnogo mozga.

The article refers to actual problems of forensic diagnostics of diffuse axonal brain injury in the acute post-traumatic period, that is of particular importance in the case of head trauma in conditions of non-evidence. To solve the existing problems, it is necessary to conduct a comprehensive study aimed at improving the diffuse axonal brain injury examination by developing a unified methodological approach to running the forensic medical diagnostics of this form of traumatic brain injury and determining the duration of the acute (up to three days) post-traumatic period.

Diffuse Axonal Injury: Clinical Prognostic Factors, Molecular Experimental Models and the Impact of the Trauma Related Oxidative Stress. An Extensive Review Concerning Milestones and Advances.

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.

Early computed tomography for acute post-traumatic diffuse axonal injury: a systematic review.

PURPOSE: Diffuse axonal injury (DAI) is the rupture of multiple axons due to acceleration and deceleration forces during a closed head injury. Most traumatic brain injuries (TBI) have some degree of DAI, especially severe TBI. Computed tomography (CT) remains the first imaging test performed in the acute phase of TBI, but has low sensitivity for detecting DAI, since DAI is a cellular lesion. The aim of this study is to search in the literature for CT signs, in the first 24 h after TBI, that may help to differentiate patients in groups with a better versus worst prognosis. METHODS: We searched for primary scientific articles in the PubMed database, in English, indexed since January 1st, 2000. RESULTS: Five articles were selected for review. In the DAI group, traffic accidents accounted 70% of the cases, 79% were male, and the mean age was 41 years. There was an association between DAI and intraventricular hemorrhage (IVH) and traumatic subarachnoid hemorrhage (tSAH); an association between the IVH grade and number of corpus callosum lesions; and an association between blood in the interpeduncular cisterns (IPC) and brainstem lesions. CONCLUSION: In closed TBI with no tSAH, severe DAI is unlikely. Similarly, in the absence of IVH, any DAI is unlikely. If there is IVH, patients generally are clinically worse; and the more ventricles affected, the worse the prognosis.

Diagnostic Approach to Traumatic Axonal Injury of the Optic Radiation in Mild Traumatic Brain Injury.

We describe a diffusion tensor tractography-based diagnostic approach to traumatic axonal injury of the optic radiation in a patient who showed visual field defect after mild traumatic brain injury. A 43-yr-old female patient experienced head trauma during a motor vehicle accident. After the head trauma, she noticed visual disturbance. Peripheral field defects were detected in both eyes on the Humphrey visual field test. After diffusion tensor tractography-based reconstruction of the optic radiation, We determined the fractional anisotropy and fiber number of each whole optic radiation. Four regions of interest were placed on the optic radiations based on diffusion tensor tractography configuration. The right optic radiation showed narrowing, and the left optic radiation revealed partial tearing in the posterior portion. The fiber number of the right optic radiation was more than two standard deviations lower than the control mean. The fractional anisotropy values of the regions of interest 2 (the narrowed area of the right optic radiation) and regions of interest 3 (the partially torn area of the left optic radiation) were more than two standard deviations lower than the control mean. Our results suggest that analysis of the configuration and parameters of the optic radiation based on three-dimensionally reconstructed diffusion tensor tractography results is a useful technique in the detection of traumatic axonal injury of the optic radiation in individual patients with mild traumatic brain injury.

Traumatic axonal injury revealed by postmortem magnetic resonance imaging: A case report.

In forensic investigations, it is important to detect traumatic axonal injuries (TAIs) to reveal head trauma that might otherwise remain occult. These lesions are subtle and frequently ambiguous on macroscopic evaluations. We present a case of TAI revealed by pre-autopsy postmortem magnetic resonance imaging (PMMR). A man in his sixties was rendered unconscious in a motor vehicle accident. CT scans revealed traumatic mild subarachnoid hemorrhage. Two weeks after the accident he regained consciousness, but displayed an altered mental state. Seven weeks after the accident, he suddenly died in hospital. Postmortem computed tomography (PMCT) and PMMR were followed by a forensic autopsy. PMMR showed low-intensity lesions in parasagittal white matter, deep white matter, and corpus callosum on three-dimensional gradient-echo T1-weighted imaging (3D-GRE T1WI). In some of these lesions, T2∗-weighted imaging also showed low-intensity foci suggesting hemorrhagic axonal injury. The lesions were difficult to find on PMCT and macroscopic evaluation, but were visible on antemortem MRI and confirmed as TAIs on histopathology. From this case, it can be said that PMMR can detect subtle TAIs missed by PMCT and macroscopic evaluation. Hence, pre-autopsy PMMR scanning could be useful for identifying TAIs during forensic investigations.

Predictive value of early MRI findings on neurocognitive and psychiatric outcomes in patients with severe traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is the major public health problem worldwide, particularly in the Middle East. Diffuse axonal injury (DAI) is commonly found in TBI. Although DAI can lead to physical and psychosocial disabilities, its prognostic value is still a matter of debate. Magnetic Resonance (MR) is more sensitive for detecting DAI lesions. OBJECTIVE: To identify the radiological and clinical factors associated with the functional capacity one year after the traumatic brain injury. METHODS: The study included 251 patients with severe head trauma for whom Brain MRI was done within one month after injury. Demographic, clinical, and radiological data were collected during hospitalization. Neurocognitive and psychiatric evaluation were done one year thereafter. RESULTS: DAI was more frequent in our patients. Psychiatric disorders, cognitive impairment, and poor functional outcome were more common in patients with DAI especially those with cerebral hemisphere and brain stem lesion, and mixed lesions. Duration of post traumatic amnesia (DPTA), lost consciousness and hospital stay (DHS) as well as the volume of diffuse axonal injury (DAI) were associated with poor neurocognitive outcome. DPTA, and DAIV may be considered independent factors that could predict the neurocognitive outcome. CONCLUSION: MRI following traumatic brain injury yields important prognostic information, with several lesion patterns significantly associated with poor long-term neurocognitive and psychiatric outcomes.

Proteomic Profiling of Mouse Brains Exposed to Blast-Induced Mild Traumatic Brain Injury Reveals Changes in Axonal Proteins and Phosphorylated Tau.

Alzheimer's disease (AD), the most prevalent form of dementia, is characterized by two pathological hallmarks: Tau-containing neurofibrillary tangles and amyloid-ß protein (Aß)-containing neuritic plaques. The goal of this study is to understand mild traumatic brain injury (mTBI)-related brain proteomic changes and tau-related biochemical adaptations that may contribute to AD-like neurodegeneration. We found that both phosphorylated tau (p-tau) and the ratio of p-tau/tau were significantly increased in brains of mice collected at 3 and 24 h after exposure to 82-kPa low-intensity open-field blast. Neurological deficits were observed in animals at 24 h and 7 days after the blast using Simple Neuroassessment of Asymmetric imPairment (SNAP) test, and axon/dendrite degeneration was revealed at 7 days by silver staining. Liquid chromatography-mass spectrometry (LC-MS/MS) was used to analyze brain tissue labeled with isobaric mass tags for relative protein quantification. The results from the proteomics and bioinformatic analysis illustrated the alterations of axonal and synaptic proteins in related pathways, including but not being limited to substantia nigra development, cortical cytoskeleton organization, and synaptic vesicle exocytosis, suggesting a potential axonal damage caused by blast-induced mTBI. Among altered proteins found in brains suffering blast, microtubule-associated protein 1B, stathmin, neurofilaments, actin binding proteins, myelin basic protein, calcium/calmodulin-dependent protein kinase, and synaptotagmin I were representative ones involved in altered pathways elicited by mTBI. Therefore, TBI induces elevated phospho-tau, a pathological feature found in brains of AD, and altered a number of neurophysiological processes, supporting the notion that blast-induced mTBI as a risk factor contributes to AD pathogenesis. LC/MS-based profiling has presented candidate target/pathways that could be explored for future therapeutic development.

Impaired cerebral compensatory reserve is associated with admission imaging characteristics of diffuse insult in traumatic brain injury.

BACKGROUND: Continuous assessment of cerebral compensatory reserve is possible using the moving correlation between pulse amplitude of intra-cranial pressure (AMP) and intra-cranial pressure (ICP), called RAP. Little is known about the behavior and associations of this index in adult traumatic brain injury (TBI). The goal of this study is to evaluate the association between admission cerebral imaging findings and RAP over the course of the acute intensive care unit stay. METHODS: We retrospectively reviewed 358 adult TBI patients admitted to the Addenbrooke's Hospital, University of Cambridge, from March 2005 to December 2016. Only non-craniectomy patients were studied. Using archived high frequency physiologic signals, RAP was derived and analyzed over the first 48 h and first 10 days of recording in each patient, using grand mean, percentage of time above various thresholds, and integrated area under the curve (AUC) of RAP over time. Associations between these values and admission computed tomography (CT) injury characteristics were evaluated. RESULTS: The integrated AUC, based on various thresholds of RAP, was statistically associated with admission CT markers of diffuse TBI and cerebral edema. Admission CT findings of cortical gyral effacement, lateral ventricle compression, diffuse cortical subarachnoid hemorrhage (SAH), thickness of cortical SAH, presence of bilateral contusions, and subcortical diffuse axonal injury (DAI) were all associated with AUC of RAP over time. Joncheere-Terpstra testing indicated a statistically significant increase in mean RAP AUC across ordinal categories of the abovementioned associated CT findings. CONCLUSIONS: RAP is associated with cerebral CT injury patterns of diffuse injury and edema, providing some confirmation of its potential measurement of cerebral compensatory reserve in TBI.

A study on correlation of pedestrian head injuries with physical parameters using in-depth traffic accident data and mathematical models.

The objective of the present study is to predict brain injuries and injury severities from realworld traffic accidents via in-depth investigation of head impact responses, injuries and brain injury tolerances. Firstly, a total of 43 passenger car versus adult pedestrian accidents were selected from two databases of the In-depth Investigation of Vehicle Accidents in Changsha of China (IVAC) and the German In-Depth Accident Study (GIDAS). In a previous study the 43 accidents were reconstructed by using the multi-body system (MBS) model (Peng et al., 2013a) for determining the initial conditions of the head-windscreen impact in each accident. Then, a study of the head injuries and injury mechanisms is carried out via 43 finite element (FE) modelings of a head strike to a windscreen, in which the boundary and loading conditions are defined according to results from accident reconstructions, including impact velocity, position and orientation of the head FE model. The brain dynamic responses were calculated for the physical parameters of the coup/countercoup pressure, von Mises and maximum shear stresses at the cerebrum, the callosum, the cerebellum and the brain stem. In addition, head injury criteria, including the cumulative strain damage measure (CSDM) (with tissue level strain threshold 0.20) and the dilatational damage measure (DDM), were developed in order to predict the diffuse axonal injury (DAI) and contusions, respectively. The correlations between calculated parameters and brain injuries were determined via comparing the simulation results with the observed injuries in accident data. The regression models were developed for predicting the injury risks in terms of the brain dynamic responses and the calculated CSDM and DDM values. The results indicate that the predicted values of 50% probability causing head injuries in the Abbreviated Injury Scale (AIS) 2+ correspond to coup pressure 167 kPa, countercoup pressure -117 kPa, von Mises 16.3 kPa and shear stress 7.9 kPa respectively, and causing AIS 3+ head injuries were 227 kPa, -169 kPa, 24.2 kPa and 12.2 kPa respectively. The results also suggest that a 50% probability of contusions corresponds to CSDM value of 48% at strain levels of 0.2, and the 50% probability of contusions corresponds to a DDM value of 6.7%.

Intensity Specific Repetitive Mild Traumatic Brain Injury Evokes an Exacerbated Burden of Neocortical Axonal Injury.

Mild traumatic brain injury (mTBI) has been linked to enduring neurological damage following repetitive injury. Previously, we reported that intensity-specific, repetitive mTBI exacerbated microvascular and axonal damage in brainstem. For a more rigorous and global assessment, we assessed the burden of neocortical diffuse axonal injury (DAI) evoked by repetitive mTBI. Mice were subjected to mild central fluid percussion injuries at 1.4 and 1.6 atm with or without repetitive insult at a 3-hour interval and killed at 24 hours postinjury. Neocortical DAI within layer V was quantitatively assessed by double-labeling p-c-Jun and NeuN to identify both the axotomized and total neuronal population. Both confocal and electron microscopic findings revealed no apparent evidence of neuronal death. Repetitive mTBI of 1.6 atm group, but not of 1.4 atm group, demonstrated a significantly higher proportion of axotomized neurons. These results demonstrate that different intensities of mTBI induced different burdens of DAI after repetitive insult. Interestingly, the parallel loss of the righting reflex reflected differences in injury intensity, yet the duration of this reflex was not elongated by the repetitive insult. These data highlight some of the complex issues surrounding repetitive mTBI and its associated morbidity, mandating the need for continued exploration.

Patients with Diffuse Axonal Injury Can Recover to a Favorable Long-Term Functional and Quality of Life Outcome.

Functional outcome and quality of life are difficult to predict in patients with diffuse axonal injury (DAI) after traumatic brain injury (TBI). The primary aim of this cross-sectional cohort study was to assess the long-term functional outcome in patients with DAI and to identify prognostic factors. Second, health-related quality of life (HRQL) at long-term follow-up was assessed. Patients ≥16 years of age with TBI and DAI (admitted 2008-2014) were included. Clinical and imaging data were collected. The primary outcome parameter was the Glasgow Outcome Scale Extended (GOSE) at long-term follow-up. Second, the HRQL was assessed with the Quality Of Life after Brain Injury (QOLIBRI) questionnaire. DAI was diagnosed in 185 patients. Long-term functional outcome was obtained in 134 patients (72%), median follow-up was 54 months (range 14-100); and 51% had a favorable outcome (GOSE 6-8). Independent prognostic factors were age, pupillary reaction, Hb, DAI grading, and return of consciousness ≤7 days. Sixty-two percent had a good HRQL, after a median follow-up of 57 months (range 14-100) with age as an independent prognostic factor. More than half of patients with DAI had a favorable functional outcome and a good HRQL at long-term follow-up. Also in patients with a DAI grade 3, a favorable outcome was seen. HRQL is a clinically relevant outcome measure because it reflects perceived outcome by patients. Independent prognostic variables for functional outcome were factors obtained in the acute phase after injury, whereas age was an independent prognostic factor for HRQL.

A case report of B lymphoblastic lymphoma with brain metastases: Clinical and pathological significance of head trauma misdiagnosis.

INTRODUCTION: B lymphoblastic lymphoma (B-LBL) is a rare type of lymphoma that originates from precursor lymphocytes. B-BLB in adults with brain metastases is extremely rare as the disease mainly affects children and adults. Therefore, such a seldom-seen case can easily trigger a dispute regarding clinical diagnosis and treatment.This paper reports the case of a 22-year-old man hospitalized for a head injury that resulted from a physical altercation. Upon admission to the hospital, the patient was diagnosed with a diffuse axonal injury (DAI). Accordingly, the patient receiving follow-up treatments, but died 30 days later. After a systematic necropsy, immunohistochemical staining, radiological consultation, and a complete review of the clinical dates, we defined the case as a brain metastasis of B lymphoblastic lymphoma. Imaging results of the intracranial lymphoma were nearly indistinguishable from DAI during the acute phase, which led to misdiagnosis and incorrect treatment for B-LBL. CONCLUSION: We present this case to broaden the scope of pathologic and clinical diagnosis for intracranial tumors and to inform physicians, general neurologists, and even medical examiners with an added degree of differential awareness in dealing with the clinical materials before further diacrisis and disposal.

Whole Brain Magnetic Resonance Spectroscopic Determinants of Functional Outcomes in Pediatric Moderate/Severe Traumatic Brain Injury.

Diffuse axonal injury contributes to the long-term functional morbidity observed after pediatric moderate/severe traumatic brain injury (msTBI). Whole-brain proton magnetic resonance echo-planar spectroscopic imaging was used to measure the neurometabolite levels in the brain to delineate the course of disruption/repair during the first year post-msTBI. The association between metabolite biomarkers and functional measures (cognitive functioning and corpus callosum [CC] function assessed by interhemispheric transfer time [IHTT] using an event related potential paradigm) was also explored. Pediatric patients with msTBI underwent assessments at two times (post-acutely at a mean of three months post-injury, n = 31, and chronically at a mean of 16 months post-injury, n = 24). Healthy controls also underwent two evaluations, approximately 12 months apart. Post-acutely, in patients with msTBI, there were elevations in choline (Cho; marker for inflammation and/or altered membrane metabolism) in all four brain lobes and the CC and decreases in N-acetylaspartate (NAA; marker for neuronal and axonal integrity) in the CC compared with controls, all of which normalized by the chronic time point. Subgroups of TBI showed variable patterns chronically. Patients with slow IHTT had lower lobar Cho chronically than those with normal IHTT; they also did not show normalization in CC NAA whereas those with normal IHTT showed significantly higher levels of CC NAA relative to controls. In the normal IHTT group only, chronic CC Cho and NAA together explained 70% of the variance in long-term cognitive functioning. MR based whole brain metabolic evaluations show different patterns of neurochemistry after msTBI in two subgroups with different outcomes. There is a dynamic relationship between prolonged inflammatory responses to brain damage, reparative processes/remyelination, and subsequent neurobehavioral outcomes. Multimodal studies allow us to test hypotheses about degenerative and reparative processes in patient groups that have divergent functional outcome, with the ultimate goal of developing targeted therapeutic agents.

Diffuse axonal injury after traumatic brain injury is a prognostic factor for functional outcome: a systematic review and meta-analysis.

OBJECTIVE: To determine the prognosis of adult patients with traumatic brain injury (TBI) and diffuse axonal injury (DAI). METHODS: Online search (PubMed, Embase and Ovid Science Direct) of articles providing information about outcome in (1) patients with DAI in general, (2) DAI vs. non-DAI, (3) related to magnetic resonance imaging (MRI) classification and (4) related to lesion location/load. A reference check and quality assessment were performed. RESULTS: A total of 32 articles were included. TBI patients with DAI had a favourable outcome in 62%. The risk of unfavourable outcome in TBI with DAI was three times higher than in TBI without DAI. Odds ratio (OR) for unfavourable outcome was 2.9 per increase of DAI grade on MRI. Lesions located in the corpus callosum were associated with an unfavourable outcome. Other specific lesion locations and lesions count showed inconsistent results regarding outcome. Lesion volume was predictive for outcome only on apparent diffusion coefficient and fluid attenuation inversion recovery MRI sequences. CONCLUSIONS: Presence of DAI on MRI in patients with TBI results in a higher chance of unfavourable outcome. With MRI grading, OR for unfavourable outcome increases threefold with every grade. Lesions in the corpus callosum in particular are associated with an unfavourable outcome.

"Don't lose hope early": Hemorrhagic diffuse axonal injury on head computed tomography is not associated with poor outcome in moderate to severe traumatic brain injury patients.

BACKGROUND: Diffuse axonal injury (DAI) on magnetic resonance imaging has been associated with poor functional outcome after moderate-severe traumatic brain injury (msTBI). Yet, DAI assessment with highly sensitive magnetic resonance imaging techniques is unfeasible in the acute trauma setting, and computed tomography (CT) remains the key diagnostic modality despite its lower sensitivity. We sought to determine whether CT-defined hemorrhagic DAI (hDAI) is associated with discharge and favorable 3- and 12-month functional outcome (Glasgow Coma Scale score ≥4) after msTBI. METHODS: We analyzed 361 msTBI patients from the single-center longitudinal Outcome Prognostication in Traumatic Brain Injury study collected over 6 years (November 2009 to November 2015) with prospective outcome assessments at 3 months and 12 months. Patients with microhemorrhages on CT were designated "CT-hDAI-positive" and those without as "CT-hDAI-negative." For secondary analyses "CT-hDAI-positive" was stratified into two phenotypes according to presence ("associated") versus absence ("predominant") of concomitant large acute traumatic lesions to determine whether presence versus absence of additional focal mass lesions portends a different prognosis. RESULTS: Seventy (19%) patients were CT-hDAI-positive (n = 36 predominant; n = 34 associated hDAI). In univariate analyses, CT-hDAI-positive status was associated with discharge survival (p = 0.004) and favorable outcome at 3 months (p = 0.003) and 12 months (p = 0.005). After multivariable adjustment, CT-hDAI positivity was no longer associated with discharge survival and functional outcome (all ps > 0.05). Stratified by hDAI phenotype, predominant hDAI patients had worse trauma severity, longer intensive care unit stays, and more systemic medical complications. Predominant hDAI, but not associated hDAI, was an independent predictor of discharge survival (adjusted odds ratio, 24.7; 95% confidence interval [CI], 3.2-192.6; p = 0.002) and favorable 12-month outcome (adjusted odds ratio, 4.7; 95% CI, 1.5-15.2; p = 0.01). Sensitivity analyses using Cox regression confirmed this finding for 1-year survival (adjusted hazard ratio, 5.6; 95% CI, 1.3-23; p = 0.048). CONCLUSION: The CT-defined hDAI was not an independent predictor of unfavorable short- and long-term outcomes and should not be used for acute prognostication in msTBI patients. Predominant hDAI patients had good clinical outcomes when supported to intensive care unit discharge and beyond. LEVEL OF EVIDENCE: Prognostic study, level III.

Mild Traumatic Brain Injury Induces Structural and Functional Disconnection of Local Neocortical Inhibitory Networks via Parvalbumin Interneuron Diffuse Axonal Injury.

Diffuse axonal injury (DAI) plays a major role in cortical network dysfunction posited to cause excitatory/inhibitory imbalance after mild traumatic brain injury (mTBI). Current thought holds that white matter (WM) is uniquely vulnerable to DAI. However, clinically diagnosed mTBI is not always associated with WM DAI. This suggests an undetected neocortical pathophysiology, implicating GABAergic interneurons. To evaluate this possibility, we used mild central fluid percussion injury to generate DAI in mice with Cre-driven tdTomato labeling of parvalbumin (PV) interneurons. We followed tdTomato+ profiles using confocal and electron microscopy, together with patch-clamp analysis to probe for DAI-mediated neocortical GABAergic interneuron disruption. Within 3 h post-mTBI tdTomato+ perisomatic axonal injury (PSAI) was found across somatosensory layers 2-6. The DAI marker amyloid precursor protein colocalized with GAD67 immunoreactivity within tdTomato+ PSAI, representing the majority of GABAergic interneuron DAI. At 24 h post-mTBI, we used phospho-c-Jun, a surrogate DAI marker, for retrograde assessments of sustaining somas. Via this approach, we estimated DAI occurs in ~9% of total tdTomato+ interneurons, representing ~14% of pan-neuronal DAI. Patch-clamp recordings of tdTomato+ interneurons revealed decreased inhibitory transmission. Overall, these data show that PV interneuron DAI is a consistent and significant feature of experimental mTBI with important implications for cortical network dysfunction.