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Mild traumatic brain injury (mTBI) can cause meningeal vascular injury and cell death that spreads into the brain parenchyma and triggers local inflammation and recruitment of peripheral immune cells. The factors that dictate meningeal recovery after mTBI are unknown at present. Here we demonstrated that most patients who had experienced mTBI resolved meningeal vascular damage within 2–3 weeks, although injury persisted for months in a subset of patients. To understand the recovery process, we studied a mouse model of mTBI and found extensive meningeal remodeling that was temporally reliant on infiltrating myeloid cells with divergent functions. Inflammatory myelomonocytic cells scavenged dead cells in the lesion core, whereas wound-healing macrophages proliferated along the lesion perimeter and promoted angiogenesis through the clearance of fibrin and production of the matrix metalloproteinase MMP-2. Notably, a secondary injury experienced during the acute inflammatory phase aborted this repair program and enhanced inflammation, but a secondary injury experienced during the wound-healing phase did not. Our findings demonstrate that meningeal vasculature can undergo regeneration after mTBI that is dependent on distinct myeloid cell subsets. Meningeal vascular damage accompanies mild traumatic brain injury, which persists in a fraction of patients. McGavern and colleagues report that distinct myeloid cell subsets are temporally recruited to the wound site during tissue repair; however, re-injury at early time points impairs recovery.

Using long-term intravital photography to explore the cellular changes after compression-induced traumatic brain injury in a murine model, it is shown that parenchymal and meningeal inflammation as well as cell death can be modulated by topical treatment with purinergic receptor antagonists and glutathione. Treating brain trauma Traumatic brain injury, often a consequence of road accidents, is a major killer and cause of neurological disorders. This study describes a closed-skull mouse model with a pathology resembling mild traumatic brain injury in humans. The authors use long-term intravital microscopy to study the dynamics of the injury response from its inception. Using the model they show that parenchymal and meningeal cell death can be reduced by topical treatment with purinergic receptor antagonists and the antioxidant glutathione. Traumatic brain injury (TBI) is increasingly appreciated to be highly prevalent and deleterious to neurological function 1 , 2 . At present, no effective treatment options are available, and little is known about the complex cellular response to TBI during its acute phase. To gain insights into TBI pathogenesis, we developed a novel murine closed-skull brain injury model that mirrors some pathological features associated with mild TBI in humans and used long-term intravital microscopy to study the dynamics of the injury response from its inception. Here we demonstrate that acute brain injury induces vascular damage, meningeal cell death, and the generation of reactive oxygen species (ROS) that ultimately breach the glial limitans and promote spread of the injury into the parenchyma. In response, the brain elicits a neuroprotective, purinergic-receptor-dependent inflammatory response characterized by meningeal neutrophil swarming and microglial reconstitution of the damaged glial limitans. We also show that the skull bone is permeable to small-molecular-weight compounds, and use this delivery route to modulate inflammation and therapeutically ameliorate brain injury through transcranial administration of the ROS scavenger, glutathione. Our results shed light on the acute cellular response to TBI and provide a means to locally deliver therapeutic compounds to the site of injury.

Traumatic meningeal enhancement (TME) is a novel biomarker observed on post-contrast fluid-attenuated inversion recovery (FLAIR) in patients who undergo contrast-enhanced magnetic resonance imaging (MRI) after suspected traumatic brain injury (TBI). TME may be seen on acute MRI despite the absence of other trauma-related intracranial findings. In this study we compare conspicuity of TME on FLAIR post-contrast and T1 weighted imaging (T1WI) post-contrast, and investigate if TME is best detected by FLAIR post-contrast or T1WI post-contrast sequences. Subjects selected for analysis enrolled in the parent study (NCT01132937) in 2016 and underwent contrast-enhanced MRI within 48 hours of suspected TBI. Two blinded readers reviewed pairs of pre- and post-contrast T1WI and FLAIR images for presence or absence of TME. Discordant pairs between the two blinded readers were reviewed by a third reader. Cohen’s kappa coefficient was used to calculate agreement. Twenty-five subjects (15 males, 10 females; median age 48 (Q1:35-Q3:62; IQR: 27)) were included. The blinded readers had high agreement for presence of TME on FLAIR (Kappa of 0.90), but had no agreement for presence of TME on T1WI (Kappa of -0.24). The FLAIR and T1WI scans were compared among all three readers and 62% of the cases positive on FLAIR could be seen on T1WI. However, 38% of the cases who were read positive on FLAIR for TME were read negative for TME on T1WI. Conspicuity of TME is higher on post-contrast FLAIR MRI than on post-contrast T1WI. TME as seen on post-contrast FLAIR MRI can aid in the identification of patients with TBI.

Cerebrovascular injuries can cause severe edema and inflammation that adversely affect human health. Here, we observed that recanalization after successful endovascular thrombectomy for acute large vessel occlusion was associated with cerebral edema and poor clinical outcomes in patients who experienced hemorrhagic transformation. To understand this process, we developed a cerebrovascular injury model using transcranial ultrasound that enabled spatiotemporal evaluation of resident and peripheral myeloid cells. We discovered that injurious and reparative responses diverged based on time and cellular origin. Resident microglia initially stabilized damaged vessels in a purinergic receptor–dependent manner, which was followed by an influx of myelomonocytic cells that caused severe edema. Prolonged blockade of myeloid cell recruitment with anti-adhesion molecule therapy prevented severe edema but also promoted neuronal destruction and fibrosis by interfering with vascular repair subsequently orchestrated by proinflammatory monocytes and proangiogenic repair-associated microglia (RAM). These data demonstrate how temporally distinct myeloid cell responses can contain, exacerbate and ultimately repair a cerebrovascular injury. This study shows how different myeloid cell types contribute to damage and repair following cerebrovascular injury, a pathology common to many central nervous system disorders, and offers new therapeutic opportunities to improve clinical outcomes.

Interpretation of the extent of perfusion deficits in stroke MRI is highly dependent on the method used for analyzing the perfusion-weighted signal intensity time-series after gadolinium injection. In this study, we introduce a new model-free standardized method of temporal similarity perfusion (TSP) mapping for perfusion deficit detection and test its ability and reliability in acute ischemia. Forty patients with an ischemic stroke or transient ischemic attack were included. Two blinded readers compared real-time generated interactive maps and automatically generated TSP maps to traditional TTP/MTT maps for presence of perfusion deficits. Lesion volumes were compared for volumetric inter-rater reliability, spatial concordance between perfusion deficits and healthy tissue and contrast-to-noise ratio (CNR). Perfusion deficits were correctly detected in all patients with acute ischemia. Inter-rater reliability was higher for TSP when compared to TTP/MTT maps and there was a high similarity between the lesion volumes depicted on TSP and TTP/MTT (r(18) = 0.73). The Pearson's correlation between lesions calculated on TSP and traditional maps was high (r(18) = 0.73, p<0.0003), however the effective CNR was greater for TSP compared to TTP (352.3 vs 283.5, t(19) = 2.6, p<0.03.) and MTT (228.3, t(19) = 2.8, p<0.03). TSP maps provide a reliable and robust model-free method for accurate perfusion deficit detection and improve lesion delineation compared to traditional methods. This simple method is also computationally faster and more easily automated than model-based methods. This method can potentially improve the speed and accuracy in perfusion deficit detection for acute stroke treatment and clinical trial inclusion decision-making.

We assessed the utility of a brief MRI protocol, appropriate for the acute setting, to detect acute traumatic brain injury (TBI) in patients with suspected mild TBI (mTBI) and distinguish traumatic from nontraumatic brain injury by comparing trauma with nontrauma patients. Twenty-two patients with suspected mTBI were included in this exploratory study over a period of 9 months. Median time from injury to MR scanning was 5.4 h (interquartile range 3.6–15.3). To determine the specificity of certain findings for TBI, 61 patients presenting with suspected minor acute stroke were included as a comparative group using the same MRI methods. A selected series of MRI sequences (diffusion-weighted imaging, fluid attenuated inversion recovery [FLAIR], and T2* weighted) were independently evaluated by two neuroradiologists blinded to clinical diagnosis, for presence of specific findings. In a separate session, all cases in which at least one MRI sequence above was positive were classified as TBI, stroke, or indeterminate. Intracranial MRI abnormalities were observed in 47 (57%) of the 83 studied patients. Based on findings on MRI, 12 (55%) of 22 suspected mTBI patients were classified as having traumatic injury. Nine (47%) of the 19 suspected mTBI patients with a negative CT had findings on MRI. Abnormalities on MRI consistent with trauma were observed most frequently on postcontrast FLAIR (83%) and T2*-weighted (58%) sequences. We demonstrated the ability of a fast MRI protocol to identify trauma-related abnormalities not seen on CT, and differentiate acute trauma from nonspecific chronic disease in a blinded cohort of mTBI patients.

Subclinical cerebrovascular disease is frequently identified in neuroimaging studies and is thought to play a role in the pathogenesis of cognitive disorders. Identifying the etiologies of different types of lesions may help investigators differentiate between age-related and pathological cerebrovascular damage in cognitive aging. In this review article, we aim to describe the epidemiology and etiology of various brain magnetic resonance imaging (MRI) measures of vascular damage in cognitively normal, older adult populations. We focus here on population-based prospective cohort studies of cognitively unimpaired older adults, as well as discuss the heterogeneity of MRI findings and their relationships with cognition. This review article emphasizes the need for a better understanding of subclinical cerebrovascular disease in cognitively normal populations, in order to more effectively identify and prevent cognitive decline in our rapidly aging population.

Although the use of magnetic resonance imaging (MRI) for the diagnosis of acute stroke is increasing, this method has not proved more effective than computed tomography (CT) in the emergency setting. We aimed to prospectively compare CT and MRI for emergency diagnosis of acute stroke. We did a single-centre, prospective, blind comparison of non-contrast CT and MRI (with diffusion-weighted and susceptibility weighted images) in a consecutive series of patients referred for emergency assessment of suspected acute stroke. Scans were independently interpreted by four experts, who were unaware of clinical information, MRI-CT pairings, and follow-up imaging. 356 patients, 217 of whom had a final clinical diagnosis of acute stroke, were assessed. MRI detected acute stroke (ischaemic or haemorrhagic), acute ischaemic stroke, and chronic haemorrhage more frequently than did CT (p<0·0001, for all comparisons). MRI was similar to CT for the detection of acute intracranial haemorrhage. MRI detected acute ischaemic stroke in 164 of 356 patients (46%; 95% CI 41–51%), compared with CT in 35 of 356 patients (10%; 7–14%). In the subset of patients scanned within 3 h of symptom onset, MRI detected acute ischaemic stroke in 41 of 90 patients (46%; 35–56%); CT in 6 of 90 (7%; 3–14%). Relative to the final clinical diagnosis, MRI had a sensitivity of 83% (181 of 217; 78–88%) and CT of 26% (56 of 217; 20–32%) for the diagnosis of any acute stroke. MRI is better than CT for detection of acute ischaemia, and can detect acute and chronic haemorrhage; therefore it should be the preferred test for accurate diagnosis of patients with suspected acute stroke. Because our patient sample encompassed the range of disease that is likely to be encountered in emergency cases of suspected stroke, our results are directly applicable to clinical practice.

Accurate diagnosis of traumatic brain injury (TBI) is critical to ensure that patients receive appropriate follow-up care, avoid risk of subsequent injury, and are aware of possible long-term consequences. However, diagnosis of TBI, particularly in the emergency department (ED), can be difficult because the symptoms of TBI are vague and nonspecific, and patients with suspected TBI may present with additional injuries that require immediate medical attention. We performed a retrospective chart review to evaluate accuracy of TBI diagnosis in the ED. Records of 1641 patients presenting to the ED with suspected TBI and a head computed tomography (CT) were reviewed. We found only 47% of patients meeting the American Congress of Rehabilitation Medicine criteria for TBI received a documented ED diagnosis of TBI in medical records. After controlling for demographic and clinical factors, patients presenting at a level I trauma center, with cause of injury other than fall, without CT findings of TBI, and without loss of consciousness were more likely to lack documented diagnosis despite meeting diagnostic criteria for TBI. A greater proportion of patients without documented ED diagnosis of TBI were discharged home compared to those with a documented diagnosis of TBI (58% vs. 40%; p < 0.001). Together, these data suggest that many patients who have sustained a TBI are discharged home from the ED without a documented diagnosis of TBI, and that improved awareness and implementation of diagnostic criteria for TBI is important in the ED and for in- and outpatient providers.

Injury to the meninges is not uncommon after traumatic brain injury (TBI), yet minimal research has been directed toward understanding the relevant biology. After a concussive event, the meninges are observed to abnormally enhance on post-contrast magnetic resonance imaging (MRI) in some patients, but not all. The aim of this work is to identify genes differentially expressed in patients with meningeal injury. Patients presenting to the emergency room with suspected TBI received a standard research MRI and blood draw within 48 h of injury. Two groups of patients were included: those with and without abnormal enhancement of the meninges on post-contrast MRI, both without other imaging findings. Groups were compared on microarray gene expression in peripheral blood samples using Affymetrix (Santa Clara, CA) and Partek Genomics Suite (Partek, Inc., St. Louis, MO) software (false discovery rate, <0.05). Forty patients were enrolled with a time from injury to MRI/blood draw of 16.8 h (interquartile range, 7.5–24.1). We observed 76 genes to be differentially expressed in patients with meningeal injury compared to those without, such as receptor for Fc fragment of IgA, multiple C2 domains, transmembrane 2, and G-protein-coupled receptor 27, which have been previously associated with initiating inflammatory mediators, phagocytosis, and other regulatory mechanisms. Post-contrast MRI is able to detect meningeal injury and has a unique biological signature observed through gene expression. These findings suggest that an acute inflammatory response occurs in response to injury to the meninges following a concussion.