Traumatic microbleeds suggest vascular injury and predict disability in traumatic brain injury.

Traumatic microbleeds are small foci of hypointensity seen on T2*-weighted MRI in patients following head trauma that have previously been considered a marker of axonal injury. The linear appearance and location of some traumatic microbleeds suggests a vascular origin. The aims of this study were to: (i) identify and characterize traumatic microbleeds in patients with acute traumatic brain injury; (ii) determine whether appearance of traumatic microbleeds predict clinical outcome; and (iii) describe the pathology underlying traumatic microbleeds in an index patient. Patients presenting to the emergency department following acute head trauma who received a head CT were enrolled within 48 h of injury and received a research MRI. Disability was defined using Glasgow Outcome Scale-Extended ≤6 at follow-up. All magnetic resonance images were interpreted prospectively and were used for subsequent analysis of traumatic microbleeds. Lesions on T2* MRI were stratified based on 'linear' streak-like or 'punctate' petechial-appearing traumatic microbleeds. The brain of an enrolled subject imaged acutely was procured following death for evaluation of traumatic microbleeds using MRI targeted pathology methods. Of the 439 patients enrolled over 78 months, 31% (134/439) had evidence of punctate and/or linear traumatic microbleeds on MRI. Severity of injury, mechanism of injury, and CT findings were associated with traumatic microbleeds on MRI. The presence of traumatic microbleeds was an independent predictor of disability (P < 0.05; odds ratio = 2.5). No differences were found between patients with punctate versus linear appearing microbleeds. Post-mortem imaging and histology revealed traumatic microbleed co-localization with iron-laden macrophages, predominately seen in perivascular space. Evidence of axonal injury was not observed in co-localized histopathological sections. Traumatic microbleeds were prevalent in the population studied and predictive of worse outcome. The source of traumatic microbleed signal on MRI appeared to be iron-laden macrophages in the perivascular space tracking a network of injured vessels. While axonal injury in association with traumatic microbleeds cannot be excluded, recognizing traumatic microbleeds as a form of traumatic vascular injury may aid in identifying patients who could benefit from new therapies targeting the injured vasculature and secondary injury to parenchyma.

Attenuation of Myeloid-Specific TGFß Signaling Induces Inflammatory Cerebrovascular Disease and Stroke.

RATIONALE: Cryptogenic strokes, those of unknown cause, have been estimated as high as 30% to 40% of strokes. Inflammation has been suggested as a critical etiologic factor. However, there is lack of experimental evidence. OBJECTIVE: In this study, we investigated inflammation-associated stroke using a mouse model that developed spontaneous stroke because of myeloid deficiency of TGF-ß (transforming growth factor-ß) signaling. METHODS AND RESULTS: We report that mice with deletion of Tgfbr2 in myeloid cells (Tgfbr2Myeko) developed cerebrovascular inflammation in the absence of significant pathology in other tissues, culminating in stroke and severe neurological deficits with 100% penetrance. The stroke phenotype can be transferred to syngeneic wild-type mice via Tgfbr2Myeko bone marrow transplant and can be rescued in Tgfbr2Myeko mice with wild-type bone marrow. The underlying mechanisms involved an increased type 1 inflammation and cerebral endotheliopathy, characterized by elevated NF-κB (nuclear factor-κB) activation and TNF (tumor necrosis factor) production by myeloid cells. A high-fat diet accelerated stroke incidence. Anti-TNF treatment, as well as metformin and methotrexate, which are associated with decreased stroke risk in population studies, delayed stroke occurrence. CONCLUSIONS: Our studies show that TGF-ß signaling in myeloid cells is required for maintenance of vascular health and provide insight into inflammation-mediated cerebrovascular disease and stroke.

Effects of increasing IV tPA-treated stroke mimic rates at CT-based centers on clinical outcomes.

OBJECTIVE: To determine to what degree stroke mimics skew clinical outcomes and the potential effects of incorrect stroke diagnosis. METHODS: This retrospective analysis of data from 2005 to 2014 included IV tissue plasminogen activator (tPA)-treated adults with clinical suspicion for acute ischemic stroke who were transferred or admitted directly to our 2 hub hospitals. Primary outcome measures compared CT-based spoke hospitals' and MRI-based hub hospitals' mimic rates, hemorrhagic transformation, follow-up modified Rankin Scale (mRS), and discharge disposition. Secondary outcomes were compared over time. RESULTS: Of the 725 thrombolysis-treated patients, 29% were at spoke hospitals and 71% at hubs. Spoke hospital patients differed from hubs by age (mean 62 ± 15 vs 72 ± 15 years, p < 0.0001), risk factors (atrial fibrillation, 17% vs 32%, p < 0.0001; alcohol consumption, 9% vs 4%, p = 0.007; smoking, 23% vs 13%, p = 0.001), and mimics (16% vs 0.6%, p < 0.0001). Inclusion of mimics resulted in better outcomes for spokes vs hubs by mRS ≤1 (40% vs 27%, p = 0.002), parenchymal hematoma type 2 (3% vs 7%, p = 0.037), and discharge home (47% vs 37%, p = 0.01). Excluding mimics, there were no significant differences. Comparing epochs, spoke stroke mimic rate doubled (9%-20%, p = 0.03); hub rate was unchanged (0%-1%, p = 0.175). CONCLUSIONS: Thrombolysis of stroke mimics is increasing at our CT-based spoke hospitals and not at our MRI-based hub hospitals. Caution should be used in interpreting clinical outcomes based on large stroke databases when stroke diagnosis at discharge is unclear. Inadvertent reporting of treated stroke mimics as strokes will artificially elevate overall favorable clinical outcomes with additional downstream costs to patients and the health care system.

Transcranial amelioration of inflammation and cell death after brain injury.

Traumatic brain injury (TBI) is increasingly appreciated to be highly prevalent and deleterious to neurological function. 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.

Whole-brain arterial spin labeling perfusion MRI in patients with acute stroke.

BACKGROUND AND PURPOSE: Perfusion MRI can be used to identify patients with acute ischemic stroke who may benefit from reperfusion therapies. The risk of nephrogenic systemic fibrosis, however, limits the use of contrast agents. Our objective was to evaluate the ability of arterial spin labeling (ASL), an alternative noninvasive perfusion technique, to detect perfusion deficits compared with dynamic susceptibility contrast (DSC) perfusion imaging. METHODS: Consecutive patients referred for emergency assessment of suspected acute stroke within a 7-month period were imaged with both ASL and DSC perfusion MRI. Images were interpreted in a random order by 2 experts blinded to clinical information for image quality, presence of perfusion deficits, and diffusion-perfusion mismatches. RESULTS: One hundred fifty-six patients were scanned with a median time of 5.6 hours (range, 3.0-17.7 hours) from last seen normal. Stroke diagnosis was clinically confirmed in 78 patients. ASL and DSC imaging were available in 64 of these patients. A perfusion deficit was detected with DSC in 39 of these patients; ASL detected 32 of these index perfusion deficits, missing 7 lesions. The median volume of the perfusion deficits as determined with DSC was smaller in patients who were evaluated as normal with ASL than in those with a deficit (median [interquartile range], 56 [10-116] versus 114 [41-225] mL; P=0.01). CONCLUSIONS: ASL can depict large perfusion deficits and perfusion-diffusion mismatches in correspondence with DSC. Our findings show that a fast 2½-minute ASL perfusion scan may be adequate for screening patients with acute stroke with contraindications to gadolinium-based contrast agents.

Measurement of glutathione in normal volunteers and stroke patients at 3T using J-difference spectroscopy with minimized subtraction errors.

PURPOSE: To develop and optimize a (1)H magnetic resonance spectroscopy (MRS) method for measuring brain glutathione (GSH) levels. MATERIALS AND METHODS: Phantom experiments and density operator simulations were performed to determine the optimal TE for measuring GSH at 3T using J-difference spectral editing. In vivo data collected from 11 normal volunteers (43 measurements) and five stroke patients (10 measurements) were processed using a new spectral alignment method (adaptive spectral registration). RESULTS: In phantom experiments and density operator simulations where relaxation effects were ignored, close to maximum GSH signal (2.95 ppm) was obtained at TE approximately 131 msec with minimum N-acetyl-aspartate (NAA) signal interference. Using adaptive spectral registration, GSH levels in healthy volunteers were found to be 1.20 +/- 0.14 mM (mean +/- standard deviation [SD]). GSH levels in stroke patients were found to be 1.19 +/- 0.24 mM in lesion and 1.25 +/- 0.19 mM in contralateral normal tissue. In comparison, the SDs were significantly larger when only the NAA singlet (2.01 ppm) was used as a navigator for spectral alignment. CONCLUSION: Spectral editing using J-differences is a reliable method for measuring GSH levels in volunteers and stroke patients.

Feridex preloading permits tracking of CNS-resident macrophages after transient middle cerebral artery occlusion.

At this time, the pathophysiology of macrophage involvement and their role in stroke progression are poorly understood. Recently, T2- and T2*-weighted magnetic resonance imaging (MRI), after intravenous administration of iron-oxide particles, have been used to understand the inflammatory cascade. Earlier studies report that image enhancement after stroke is from iron-laden macrophages; however, they do not account for potential blood-brain barrier disruption and nonspecific contrast enhancement. In this study, spontaneously hypertensive rats were preloaded with Feridex 7 days before stroke, permitting the labeling of bone-marrow-derived macrophages. Three-dimensional gradient-echo imaging showed average signal decreases of 13% to 23% in preloaded animals, concentrated on the lesion periphery and reaching a maximum on days 2 to 4 after stroke. Immunohistochemistry showed ED-2+, PB+, MHC-II+ and TNF-alpha+ perivascular macrophages (PVM), meningeal macrophages (MM), and choroid plexus macrophages (CPM). ED-1+ and IBA+ tissue macrophages and/or activated microglia were located throughout the lesion, but were PB-. These findings indicate the following: (1) Feridex preloading permits tracking of the central nervous system (CNS)-resident macrophages (PVM, MM, and CPM) and (2) CNS-resident macrophages likely play an integral role in the inflammatory cascade through antigen presentation and expression of proinflammatory cytokines. Further refinement of this method should permit noninvasive monitoring of inflammation and potential evaluation of antiinflammatory therapies in preclinical models of stroke.