David L. Brody

Detection of Blast-Related Traumatic Brain Injury in U.S. Military Personnel

BACKGROUND Blast-related traumatic brain injuries have been common in the Iraq and Afghanistan wars, but fundamental questions about the nature of these injuries remain unanswered. METHODS We tested the hypothesis that blast-related traumatic brain injury causes traumatic axonal injury, using diffusion tensor imaging (DTI), an advanced form of magnetic resonance imaging that is sensitive to axonal injury. The subjects were 63 U.S. military personnel who had a clinical diagnosis of mild, uncomplicated traumatic brain injury. They were evacuated from the field to the Landstuhl Regional Medical Center in Landstuhl, Germany, where they underwent DTI scanning within 90 days after the injury. All the subjects had primary blast exposure plus another, blast-related mechanism of injury (e.g., being struck by a blunt object or injured in a fall or motor vehicle crash). Controls consisted of 21 military personnel who had blast exposure and other injuries but no clinical diagnosis of traumatic brain injury. RESULTS Abnormalities revealed on DTI were consistent with traumatic axonal injury in many of the subjects with traumatic brain injury. None had detectable intracranial injury on computed tomography. As compared with DTI scans in controls, the scans in the subjects with traumatic brain injury showed marked abnormalities in the middle cerebellar peduncles (P<0.001), in cingulum bundles (P=0.002), and in the right orbitofrontal white matter (P=0.007). In 18 of the 63 subjects with traumatic brain injury, a significantly greater number of abnormalities were found on DTI than would be expected by chance (P<0.001). Follow-up DTI scans in 47 subjects with traumatic brain injury 6 to 12 months after enrollment showed persistent abnormalities that were consistent with evolving injuries. CONCLUSIONS DTI findings in U.S. military personnel support the hypothesis that blast-related mild traumatic brain injury can involve axonal injury. However, the contribution of primary blast exposure as compared with that of other types of injury could not be determined directly, since none of the subjects with traumatic brain injury had isolated primary blast injury. Furthermore, many of these subjects did not have abnormalities on DTI. Thus, traumatic brain injury remains a clinical diagnosis. (Funded by the Congressionally Directed Medical Research Program and the National Institutes of Health; ClinicalTrials.gov number, NCT00785304.).

Diffusion Tensor Imaging Reliably Detects Experimental Traumatic Axonal Injury and Indicates Approximate Time of Injury

Traumatic axonal injury (TAI) may contribute greatly to neurological impairments after traumatic brain injury, but it is difficult to assess with conventional imaging. We quantitatively compared diffusion tensor imaging (DTI) signal abnormalities with histological and electron microscopic characteristics of pericontusional TAI in a mouse model. Two DTI parameters, relative anisotropy and axial diffusivity, were significantly reduced 6 h to 4 d after trauma, corresponding to relatively isolated axonal injury. One to 4 weeks after trauma, relative anisotropy remained decreased, whereas axial diffusivity “pseudo-normalized” and radial diffusivity increased. These changes corresponded to demyelination, edema, and persistent axonal injury. At every time point, DTI was more sensitive to injury than conventional magnetic resonance imaging, and relative anisotropy distinguished injured from control mice with no overlap between groups. Remarkably, DTI changes strongly predicted the approximate time since trauma. These results provide an important validation of DTI for pericontusional TAI and suggest novel clinical and forensic applications.

Amyloid-β Dynamics Correlate with Neurological Status in the Injured Human Brain

The amyloid-β peptide (Aβ) plays a central pathophysiological role in Alzheimers disease, but little is known about the concentration and dynamics of this secreted peptide in the extracellular space of the human brain. We used intracerebral microdialysis to obtain serial brain interstitial fluid (ISF) samples in 18 patients who were undergoing invasive intracranial monitoring after acute brain injury. We found a strong positive correlation between changes in brain ISF Aβ concentrations and neurological status, with Aβ concentrations increasing as neurological status improved and falling when neurological status declined. Brain ISF Aβ concentrations were also lower when other cerebral physiological and metabolic abnormalities reflected depressed neuronal function. Such dynamics fit well with the hypothesis that neuronal activity regulates extracellular Aβ concentration.

Detection of traumatic axonal injury with diffusion tensor imaging in a mouse model of traumatic brain injury

Traumatic axonal injury (TAI) is thought to be a major contributor to cognitive dysfunction following traumatic brain injury (TBI), however TAI is difficult to diagnose or characterize non-invasively. Diffusion tensor imaging (DTI) has shown promise in detecting TAI, but direct comparison to histologically-confirmed axonal injury has not been performed. In the current study, mice were imaged with DTI, subjected to a moderate cortical controlled impact injury, and re-imaged 4-6 h and 24 h post-injury. Axonal injury was detected by amyloid beta precursor protein (APP) and neurofilament immunohistochemistry in pericontusional white matter tracts. The severity of axonal injury was quantified using stereological methods from APP stained histological sections. Two DTI parameters--axial diffusivity and relative anisotropy--were significantly reduced in the injured, pericontusional corpus callosum and external capsule, while no significant changes were seen with conventional MRI in these regions. The contusion was easily detectable on all MRI sequences. Significant correlations were found between changes in relative anisotropy and the density of APP stained axons across mice and across subregions spanning the spatial gradient of injury. The predictive value of DTI was tested using a region with DTI changes (hippocampal commissure) and a region without DTI changes (anterior commissure). Consistent with DTI predictions, there was histological detection of axonal injury in the hippocampal commissure and none in the anterior commissure. These results demonstrate that DTI is able to detect axonal injury, and support the hypothesis that DTI may be more sensitive than conventional imaging methods for this purpose.

Active and Passive Immunotherapy for Neurodegenerative Disorders

Immunotherapeutic strategies to combat neurodegenerative disorders have galvanized the scientific community since the first dramatic successes in mouse models recreating aspects of Alzheimer disease (AD) were reported. However, initial human trials of active amyloid-beta (Abeta) vaccination were halted early because of a serious safety issue: meningoencephalitis in 6% of subjects. Nonetheless, some encouraging preliminary data were obtained, and rapid progress has been made toward developing alternative, possibly safer active and passive immunotherapeutic approaches for several neurodegenerative conditions. Many of these are currently in human trials for AD. Despite these advances, our understanding of the essential mechanisms underlying the effects seen in preclinical models and human subjects is still incomplete. Antibody-induced phagocytosis of pathological protein deposits, direct antibody-mediated disruption of aggregates, neutralization of toxic soluble proteins, a shift in equilibrium toward efflux of specific proteins from the brain, cell-mediated immune responses, and other mechanisms may all play roles depending on the specific immunotherapeutic scenario.

Use of recombinant factor VIIa in patients with warfarin-associated intracranial hemorrhage

AbstractIntroduction: Warfarin-associated intracranial hemorrhage (ICH) requires rapid normalization of clotting function. Current therapies are associated with significant complications and/or prolonged time to correction of coagulopathy. Recombinant factor VIIa (FVIIa) might allow faster and safer correction of coagulopathy. Methods: This article presents a retrospective chart review of all patients with warfarin-associated ICH treated in a neurology/neurosurgery intensive care unit over an 11-month period. Results: All patients were treated to rapidly reverse the warfarin effect. Fifteen patients received vitamin K and fresh frozen plasma (FFP) alone (FFP group). Twelve patients also received FVIIa (FVIIa group). The median times from presentation to an international normalization ratio (INR) of less than 1.3 were 32.2 and 8.8 hours in the FFP the FVIIa groups, respectively (p=0.016). INR normalized slowly (at 110 and 130 hours, respectively) in two patients with end-stage renal failure who were given FVIIa, one of whom developed disseminated intravascular coagulation after three doses of FVIIa. No other complications occurred from FVIIa administration. One patient in the FFP group developed severe pulmonary edema. Conclusion: FVIIa may be an effective adjunct to FFP in warfarin-related ICH, facilitating faster correction of INR and decreasing FFP requirements. A prospective, randomized trial is needed to confirm these preliminary findings and to determine whether there is a clinical benefit.

Tau elevations in the brain extracellular space correlate with reduced amyloid-β levels and predict adverse clinical outcomes after severe traumatic brain injury

Axonal injury is believed to be a major determinant of adverse outcomes following traumatic brain injury. However, it has been difficult to assess acutely the severity of axonal injury in human traumatic brain injury patients. We hypothesized that microdialysis-based measurements of the brain extracellular fluid levels of tau and neurofilament light chain, two low molecular weight axonal proteins, could be helpful in this regard. To test this hypothesis, 100 kDa cut-off microdialysis catheters were placed in 16 patients with severe traumatic brain injury at two neurological/neurosurgical intensive care units. Tau levels in the microdialysis samples were highest early and fell over time in all patients. Initial tau levels were >3-fold higher in patients with microdialysis catheters placed in pericontusional regions than in patients in whom catheters were placed in normal-appearing right frontal lobe tissue (P = 0.005). Tau levels and neurofilament light-chain levels were positively correlated (r = 0.6, P = 0.013). Neurofilament light-chain levels were also higher in patients with pericontusional catheters (P = 0.04). Interestingly, initial tau levels were inversely correlated with initial amyloid-β levels measured in the same samples (r = -0.87, P = 0.000023). This could be due to reduced synaptic activity in areas with substantial axonal injury, as amyloid-β release is closely coupled with synaptic activity. Importantly, high initial tau levels correlated with worse clinical outcomes, as assessed using the Glasgow Outcome Scale 6 months after injury (r = -0.6, P = 0.018). Taken together, our data add support for the hypothesis that axonal injury may be related to long-term impairments following traumatic brain injury. Microdialysis-based measurement of tau levels in the brain extracellular space may be a useful way to assess the severity of axonal injury acutely in the intensive care unit. Further studies with larger numbers of patients will be required to assess the reproducibility of these findings and to determine whether this approach provides added value when combined with clinical and radiological information.

Rapamycin Attenuates the Development of Posttraumatic Epilepsy in a Mouse Model of Traumatic Brain Injury

Posttraumatic epilepsy is a major source of disability following traumatic brain injury (TBI) and a common cause of medically-intractable epilepsy. Previous attempts to prevent the development of posttraumatic epilepsy with treatments administered immediately following TBI have failed. Recently, the mammalian target of rapamycin complex 1 (mTORC1) pathway has been implicated in mechanisms of epileptogenesis and the mTORC1 inhibitor, rapamycin, has been proposed to have antiepileptogenic effects in preventing some types of epilepsy. In this study, we have tested the hypothesis that rapamycin has antiepileptogenic actions in preventing the development of posttraumatic epilepsy in an animal model of TBI. A detailed characterization of posttraumatic epilepsy in the mouse controlled cortical impact model was first performed using continuous video-EEG monitoring for 16 weeks following TBI. Controlled cortical impact injury caused immediate hyperactivation of the mTORC1 pathway lasting at least one week, which was reversed by rapamycin treatment. Rapamycin decreased neuronal degeneration and mossy fiber sprouting, although the effect on mossy fiber sprouting was reversible after stopping rapamycin and did not directly correlate with inhibition of epileptogenesis. Most posttraumatic seizures occurred greater than 10 weeks after TBI, and rapamycin treatment for one month after TBI decreased the seizure frequency and rate of developing posttraumatic epilepsy during the entire 16 week monitoring session. These results suggest that rapamycin may represent a rational treatment for preventing posttraumatic epilepsy in patients with TBI.

Diffusion Tensor Imaging Detects Axonal Injury in a Mouse Model of Repetitive Closed-Skull Traumatic Brain Injury

Mild traumatic brain injuries (TBI) are common in athletes, military personnel, and the elderly, and increasing evidence indicates that these injuries have long-term health effects. However, the difficulty in detecting these mild injuries in vivo is a significant impediment to understanding the underlying pathology and treating mild TBI. In the following experiments, we present the results of diffusion tensor imaging (DTI) and histological analysis of a model of mild repetitive closed-skull brain injury in mouse. Histological markers used included silver staining and amyloid precursor protein (APP) immunohistochemistry to detect axonal injury, and Iba-1 immunohistochemistry to assess microglial activation. At 24h post-injury, before silver staining or microglial abnormalities were apparent by histology, no significant changes in any of the DTI parameters were observed within white matter. At 7 days post-injury we observed a reduction in axial and mean diffusivity. Relative anisotropy at 7 days correlated strongly with the degree of silver staining. Interestingly, APP was not observed at any timepoint examined. In addition to the white matter alterations, mean diffusivity was elevated in ipsilateral cortex at 24h but returned to sham levels by 7 days. Altogether, this demonstrates that DTI is a sensitive method for detecting axonal injury despite a lack of conventional APP pathology. Further, this reflects a need to better understand the histological basis for DTI signal changes in mild TBI.

Common data elements in radiologic imaging of traumatic brain injury.

Traumatic brain injury (TBI) has a poorly understood pathology. Patients suffer from a variety of physical and cognitive effects that worsen as the type of trauma worsens. Some noninvasive insights into the pathophysiology of TBI are possible using magnetic resonance imaging (MRI), computed tomography (CT), and many other forms of imaging as well. A recent workshop was convened to evaluate the common data elements (CDEs) that cut across the imaging field and given the charge to review the contributions of the various imaging modalities to TBI and to prepare an overview of the various clinical manifestations of TBI and their interpretation. Technical details regarding state‐of‐the‐art protocols for both MRI and CT are also presented with the hope of guiding current and future research efforts as to what is possible in the field. Stress was also placed on the potential to create a database of CDEs as a means to best record information from a given patient from the reading of the images. J. Magn. Reson. Imaging 2010;32:516–543.