TLR4 mutation and HSP60-induced cell death in adult mouse cardiac myocytes.

Extracellular (ex) HSP60 is increasingly recognized as an agent of cell injury. Previously, we reported that low endotoxin exHSP60 causes cardiac myocyte apoptosis. Our findings supported a role for Toll-like receptor (TLR) 4 in HSP60 mediated apoptosis. To further investigate the involvement of TLR4 in cardiac injury, we studied adult cardiac myocytes from C3H/HeJ (HeJ) mice, which have a mutant, nonfunctional TLR4, and compared the results with parallel studies using wild-type (WT) mice. Nuclear factor κB (NFκB) activation is an early step downstream of TLR4. NFκB was activated 1 h after treatment with HSP60 in WT, but not HeJ mouse myocytes. ExHSP60 caused apoptosis in cardiac myocytes from WT mice, but not in myocytes from the HeJ mutants. To further elucidate the importance of exHSP60 in cardiac myocyte injury, both WT and HeJ mutant isolated mouse adult cardiac myocytes were exposed to hypoxia/reoxygenation. Anti-HSP60 antibody treatment reduced apoptosis in the WT group, but had no effect on the HeJ mutant myocytes. Unexpectedly, necrosis was also decreased in the HeJ mutants. Necrosis after hypoxia/reoxygenation in WT cardiac myocytes was mediated in part by TLR2 and TLR4 through rapid activation of PKCα, followed by increased expression of Nox2, and this was ameliorated by blocking antibodies to TLR2/4. These studies provide further evidence that TLR4 mediates exHSP60-associated apoptosis and that exHSP60 has an important role in cardiac myocyte injury, both apoptotic and necrotic.

Correlations between perfusion MR imaging cerebral blood volume, microvessel quantification, and clinical outcome using stereotactic analysis in recurrent high-grade glioma.

BACKGROUND AND PURPOSE: Quantifying MVA rather than MVD provides better correlation with survival in HGG. This is attributed to a specific "glomeruloid" vascular pattern, which is better characterized by vessel area than number. Despite its prognostic value, MVA quantification is laborious and clinically impractical. The DSC-MR imaging measure of rCBV offers the advantages of speed and convenience to overcome these limitations; however, clinical use of this technique depends on establishing accurate correlations between rCBV, MVA, and MVD, particularly in the setting of heterogeneous vascular size inherent to human HGG. MATERIALS AND METHODS: We obtained preoperative 3T DSC-MR imaging in patients with HGG before stereotactic surgery. We histologically quantified MVA, MVD, and vascular size heterogeneity from CD34-stained 10-µm sections of stereotactic biopsies, and we coregistered biopsy locations with localized rCBV measurements. We statistically correlated rCBV, MVA, and MVD under conditions of high and low vascular-size heterogeneity and among tumor grades. We correlated all parameters with OS by using Cox regression. RESULTS: We analyzed 38 biopsies from 24 subjects. rCBV correlated strongly with MVA (r = 0.83, P < .0001) but weakly with MVD (r = 0.32, P = .05), due to microvessel size heterogeneity. Among samples with more homogeneous vessel size, rCBV correlation with MVD improved (r = 0.56, P = .01). OS correlated with both rCBV (P = .02) and MVA (P = .01) but not with MVD (P = .17). CONCLUSIONS: rCBV provides a reliable estimation of tumor MVA as a biomarker of glioma outcome. rCBV poorly estimates MVD in the presence of vessel size heterogeneity inherent to human HGG.

Optimized preload leakage-correction methods to improve the diagnostic accuracy of dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging in posttreatment gliomas.

BACKGROUND AND PURPOSE: Relative cerebral blood volume (rCBV) accuracy can vary substantially depending on the dynamic susceptibility-weighted contrast-enhanced (DSC) acquisition and postprocessing methods, due to blood-brain barrier disruption and resulting T1-weighted leakage and T2- and/or T2*-weighted imaging (T2/T2*WI) residual effects. We set out to determine optimal DSC conditions that address these errors and maximize rCBV accuracy in differentiating posttreatment radiation effect (PTRE) and tumor. MATERIALS AND METHODS: We recruited patients with previously treated high-grade gliomas undergoing image-guided re-resection of recurrent contrast-enhancing MR imaging lesions. Thirty-six surgical tissue samples were collected from 11 subjects. Preoperative 3T DSC used 6 sequential evenly timed acquisitions, each by using a 0.05-mmol/kg gadodiamide bolus. Preload dosing (PLD) and baseline subtraction (BLS) techniques corrected T1-weighted leakage and T2/T2*WI residual effects, respectively. PLD amount and incubation time increased with each sequential acquisition. Corresponding tissue specimen stereotactic locations were coregistered to DSC to measure localized rCBV under varying PLD amounts, incubation times, and the presence of BLS. rCBV thresholds were determined to maximize test accuracy (average of sensitivity and specificity) in distinguishing tumor (n = 21) and PTRE (n = 15) samples under the varying conditions. Receiver operator characteristic (ROC) areas under the curve (AUCs) were statistically compared. RESULTS: The protocol that combined PLD (0.1-mmol/kg amount, 6-minute incubation time) and BLS correction methods maximized test AUC (0.99) and accuracy (95.2%) compared with uncorrected rCBV AUC (0.85) and accuracy (81.0%) measured without PLD and BLS (P = .01). CONCLUSIONS: Combining PLD and BLS correction methods for T1-weighted and T2/T2*WI errors, respectively, enables highly accurate differentiation of PTRE and tumor growth.

Relative cerebral blood volume values to differentiate high-grade glioma recurrence from posttreatment radiation effect: direct correlation between image-guided tissue histopathology and localized dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging measurements.

BACKGROUND AND PURPOSE: Differentiating tumor growth from posttreatment radiation effect (PTRE) remains a common problem in neuro-oncology practice. To our knowledge, useful threshold relative cerebral blood volume (rCBV) values that accurately distinguish the 2 entities do not exist. Our prospective study uses image-guided neuronavigation during surgical resection of MR imaging lesions to correlate directly specimen histopathology with localized dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging (DSC) measurements and to establish accurate rCBV threshold values, which differentiate PTRE from tumor recurrence. MATERIALS AND METHODS: Preoperative 3T gradient-echo DSC and contrast-enhanced stereotactic T1-weighted images were obtained in patients with high-grade glioma (HGG) previously treated with multimodality therapy. Intraoperative neuronavigation documented the stereotactic location of multiple tissue specimens taken randomly from the periphery of enhancing MR imaging lesions. Coregistration of DSC and stereotactic images enabled calculation of localized rCBV within the previously recorded specimen locations. All tissue specimens were histopathologically categorized as tumor or PTRE and were correlated with corresponding rCBV values. All rCBV values were T1-weighted leakage-corrected with preload contrast-bolus administration and T2/T2*-weighted leakage-corrected with baseline subtraction integration. RESULTS: Forty tissue specimens were collected from 13 subjects. The PTRE group (n = 16) rCBV values ranged from 0.21 to 0.71, tumor (n = 24) values ranged from 0.55 to 4.64, and 8.3% of tumor rCBV values fell within the PTRE group range. A threshold value of 0.71 optimized differentiation of the histopathologic groups with a sensitivity of 91.7% and a specificity of 100%. CONCLUSIONS: rCBV measurements obtained by using DSC and the protocol we have described can differentiate HGG recurrence from PTRE with a high degree of accuracy.

Hypothalamic hamartomas: Correlation of MR imaging and spectroscopic findings with tumor glial content.

BACKGROUND AND PURPOSE: There is variability in the literature concerning the appearance and histology of hypothalamic hamartomas. This study correlates the MR imaging and proton MR spectroscopic properties of hypothalamic hamartomas with histopathologic findings. METHODS: Studies were performed with 3T and 1.5T scanners. Single voxel hamartoma spectra were acquired by using short-echo-time point-resolved spectroscopy sequences (PRESS). 2D PRESS chemical shift imaging (CSI) spectroscopic sequences were also obtained for comparison of tumor-derived spectra with normal gray matter of the amygdala. Sequences were used to compare choline (Cho), N-acetylaspartate (NAA), and myoinositol (mI) resonances by using a creatine (Cr) reference. Spectral ratios and T2 signal intensity ratios of the hamartomas were then compared with histopathologic findings. RESULTS: Data from single voxel spectroscopic sequences demonstrated a statistically significant decrease in NAA/Cr and an increase in mI/Cr ratios in tumor tissue when compared with values in normal gray matter of the amygdala. In addition, Cho/Cr ratios were also increased when compared with those in normal gray matter controls. Among the 14 hamartomas sampled, a spectrum of increased mI/Cr ratios was seen. Those tumors with markedly elevated mI/Cr demonstrated an increased glial component when compared with the remaining tumors. Increased glial component was also found to have a positive correlation with hyperintensity of lesions on T2-weighted images. CONCLUSION: We have identified a correlation between the glial/neuronal fraction as determined by histopathology and MR spectral and T2 hyperintensity variations among hypothalamic hamartomas.

Diffusion-weighted imaging provides support for secondary neuronal damage from intraparenchymal hematoma.

It is controversial whether an intracerebral hematoma (ICH) causes ischemia of surrounding brain. By virtue of its high sensitivity to acute cerebral infarction, diffusion-weighted imaging (DWI) helps answer this question. We used this technique to assess the parenchyma surrounding ICH for restricted diffusion. Echoplanar DWI (b 1000 s/mm(2)) and conventional MRI sequences were performed in 30 subjects (symptom duration 7-75 h) with primary ICH, mean volume: 13+/-15 cm(3). We calculated mean apparent diffusion coefficients (ADC) within high signal regions around the hematoma on DWI or T2-weighted images and within the ICH itself, comparing them to the contralateral brain. We used the Student's t -test to examine for differences between these regions and linear regression to relate changes to the age of the ICH. A thin rim of high signal on DWI and a wider rim on T2-weighted images surrounded all hematomas. The ADC within the rim on DWI showed a maximum reduction of 40%, in two patients imaged within 10 h of symptom onset. They rose during the first day (r(2)=0.84; P <0.03) and then showed a mild decrease, becoming the same as ADC in other areas of the brain (r(2)=0.5; P <0.03). The rim on T2-weighting showed a mean increase of 50% and ADC within the ICH were reduced by a mean of 38%; these variations showed no relationship with ICH age and no group showed any relationship with ICH size. The ADC within the three regions was significantly different from each other. The presence of restricted diffusion in the parenchyma surrounding ICH provides support for secondary neuronal damage.

PROPELLER MRI: clinical testing of a novel technique for quantification and compensation of head motion.

While head motion is considered a significant problem in magnetic resonance imaging (MRI), there is no data to quantify its extent, severity, or effect on image quality. PROPELLER (Periodically Rotated Overlapping ParallEL Lines with Enhanced Reconstruction) MRI offers a novel means of quantifying and compensating for head motion. We performed axial T2-weighted PROPELLER (motion corrected: P-CR; uncorrected: P-UNCR) and conventional MRI (CONV), with equal scan times, in five normal volunteers and 35 clinical subjects. Volunteers were examined lying still and performing two separate head movements (shake "no" and nod "yes") to assess detection and compensation of in-plane motion by PROPELLER MRI. Images were examined by three radiologists for motion artifact and for overall image quality. Head rotation and translation was detected in all subjects during each slice acquisition, with expected changes occurring with volunteer head motion. Motion artifact was less commonly seen on PROPELLER than CONV MR (chi(2) test P < 0.001). PROPELLER was preferred over CONV in all subjects (P < 0.05) and P-CR was judged superior to P-UNCR (P = 0.02). Intracranial pathology was equally or better demonstrated with PROPELLER. PROPELLER MRI offers a means of quantifying head motion, reducing motion artifact, and improving image quality.

Magnetic resonance angiography and evaluation of cervical arteries.

Multiple clinical trials have demonstrated the efficacy of endarterectomy in selected groups of patients based primarily on percent diameter stenosis. Although measurement of stenosis in the clinical trials was established by conventional angiography, there is considerable interest in noninvasive alternatives. Magnetic resonance angiography, performed using time-of-flight methods or with contrast enhancement, is one of several alternatives for noninvasive carotid evaluation. Screening examinations are routinely performed for carotid stenosis. Preoperative evaluations based on one or a combination of noninvasive tests have been proposed, although these proposals are the subject of ongoing controversy. Evaluation of the vertebral arteries is more difficult and less well studied: however, the increasing availability of therapies for posterior circulation atherosclerotic narrowing is resulting in increased interest in this problem.

Assessment of silent embolism from carotid endarterectomy by use of diffusion-weighted imaging: work in progress.

BACKGROUND AND PURPOSE: Transcranial Doppler studies have suggested that microemboli are released into the arterial circulation during the majority of carotid endarterectomy (CEA) procedures. This, together with the observation that neuropsychological performance may decline postoperatively, has led to concern that cerebral infarction may occur unrecognized during CEA. Our objective was to examine this risk with diffusion-weighted imaging, a technique that is highly sensitive to acute cerebral infarction. METHODS: Eighteen participants (median age, 68 years; age range, 56-87 years) were assessed with diffusion-weighted imaging and the National Institutes of Health Stroke Scale before and after CEA. Imaging was performed using single-shot echo-planar imaging with a maximum diffusion sensitivity of b = 1000 s/mm(2) applied to three orthogonal planes. Preoperative imaging was performed a median of 2.5 hours before surgery (range, 0.5-12.5 hours) and 15 hours after surgery (range, 1.5-58.5 hours). Two neuroradiologists independently interpreted the diffusion-weighted images, blinded to operative status and clinical findings. RESULTS: There was no diffusion-weighted imaging evidence of silent embolism in this series of 18 participants (95% confidence interval limits, 0 to 10%). Clinical complications were confined to one case of confusion occurring after CEA; the diffusion-weighted imaging results were normal in this case. CONCLUSION: There is no evidence from our series that silent cerebral infarction is a common occurrence during CEA. These data provide further support for the safety of CEA.

Evidence for cytotoxic edema in the pathogenesis of cerebral venous infarction.

BACKGROUND AND PURPOSE: The pathogenesis of cerebral venous infarction (CVI) remains controversial, with uncertainty over whether cytotoxic edema plays a role. Recent animal studies have shown that cytotoxic edema reliably occurs in acute CVI and precedes the onset of vasogenic edema. Our hypothesis was that cytotoxic edema would also occur in acute human CVI and would be detectable as an area of restricted diffusion on diffusion-weighted images. METHODS: Twelve subjects with acute cerebral venous thrombosis confirmed by MR venography underwent both conventional MR and echo-planar diffusion-weighted imaging (maximum diffusion sensitivity [b=1000 s/mm(2)]). Images were examined for areas of CVI that were identified as T2 hyperintensity, diffusion hyperintensity, or hemorrhage. The percent change in apparent diffusion coefficient (ADC) and T2 signal as well as the T2/diffusion volume were calculated within areas of edematous CVI. Regression techniques were used to examine the relationship of these variables to symptom duration. RESULTS: Ten regions of CVI were detected in seven subjects, all showing T2 hyperintensity. Two of these regions were predominantly hemorrhagic and did not display diffusion hyperintensity. The remaining eight regions displayed diffusion hyperintensity that was associated with a decreased ADC. ADC values increased with symptom duration (r(2) = 0.96; P <.006). Both T2 hyperintensity and T2/diffusion volume peaked approximately 2 days after symptom onset. CONCLUSION: Restricted water diffusion suggesting cytotoxic edema is commonly found in subjects with acute CVI and decreases over time. This supports an important etiologic role for cytotoxic edema in the pathogenesis of CVI.

Effect of voxel position on single-voxel MR spectroscopy findings.

BACKGROUND AND PURPOSE: Single-voxel MR spectroscopy is a widely used tool for evaluating brain tumors. Although extensive data are available on the MR spectral appearance of tumors, less is known about the effect of voxel position on the accuracy of single-voxel MR spectroscopy findings. The purpose of this study was to test the hypothesis that the accuracy of single-voxel MR spectroscopy in the categorization of lesions as either tumor or not tumor is dependent on voxel position. METHODS: Fifty single-voxel MR spectra acquired with a fully automated stimulated-echo spectroscopy sequence were reviewed retrospectively in 43 patients with new or previously treated intra-axial brain tumors. Spectra were analyzed for the presence of choline, creatine, N-acetylaspartate (NAA), and lipid/lactate. Choline/creatine and NAA/creatine peak area ratios were assessed qualitatively. Lesions were grouped into one of three categories on the basis of spectral pattern: tumor, not tumor, or indeterminate. Results of MR spectroscopy were compared with the final histopathologic diagnosis. RESULTS: Histologic confirmation was obtained in 19 patients; MR spectra were interpretable in 17 of those. MR spectra correctly categorized nine of 17 lesions (six tumor, three nontumor). All eight misdiagnosed lesions were tumors. When the MR spectroscopy voxel included the enhancing edge of the lesion, the spectra correctly categorized seven of eight lesions (four of five tumors and all three cases of radiation necrosis). When the MR spectroscopy voxel was positioned centrally within the lesion, the spectra correctly reflected histologic outcome in two of nine lesions (all tumors). CONCLUSION: The reliability of single-voxel MR spectroscopy findings is dependent on voxel position. Spectra obtained from voxels at the enhancing edge of a tumor more accurately reflect lesion histopathology than do spectra obtained from the lesion center, even if the centrally placed voxels contain solidly enhancing tissue.

Incidence of postangiographic abnormalities revealed by diffusion-weighted MR imaging.

BACKGROUND AND PURPOSE: Occasionally we have observed anecdotal cases of asymptomatic hyperintensities on diffusion-weighted MR (DW-MR) examinations of the brain of patients who previously underwent routine cerebral angiography. These observations, as well as MR imaging and transcranial Doppler data in the literature suggesting a high rate of procedure-associated emboli, raise concern regarding the underdiagnosis of asymptomatic focal infarction associated with cerebral angiography. In order to determine whether asymptomatic diffusion abnormalities are frequently associated with procedures, we prospectively obtained DW-MR images before and after routine cerebral angiography. METHODS: Twenty consecutive patients, who met protocol criteria and received a routine three- or four-vessel diagnostic cerebral angiogram at our institution, were evaluated. Using a Bayesian estimate to establish an upper bound for the incidence of an event with zero occurrences in a study sample, the study group size was selected to exclude a 10% incidence of abnormalities revealed by DW-MR imaging of patients who underwent previous cerebral angiography. Two neuroradiologists evaluated imaging studies. RESULTS: Neither clinical signs nor abnormalities on DW-MR images were found, which suggested no infarction after angiography in our patient sample. Based on this data, an upper bound of 9% (95% confidence) is predicted for the appearance of abnormalities revealed by DW-MR imaging after cerebral angiography. CONCLUSION: Cerebral angiography is associated with an incidence of asymptomatic cerebral infarction of no more than 9%. It well may be substantially lower than this estimate; a more accurate evaluation of the true incidence would require a significantly larger study population. This test provides a convenient noninvasive means of assessing procedure-related cerebral infarction, such as that which occurs after carotid endarterectomy or vascular angioplasty and stenting.

Cerebral MR venography: normal anatomy and potential diagnostic pitfalls.

BACKGROUND AND PURPOSE: MR venography is often used to examine the intracranial venous system, particularly in the evaluation of dural sinus thrombosis. The purpose of this study was to evaluate the use of MR venography in the depiction of the normal intracranial venous anatomy and its variants, to assess its potential pitfalls in the diagnosis of dural venous sinus thrombosis, and to compare the findings with those of conventional catheter angiography. METHODS: Cerebral MR venograms obtained in 100 persons with normal MR imaging studies were reviewed to determine the presence or absence of the dural sinuses and major intracranial veins. RESULTS: Systematic review of the 100 cases revealed transverse sinus flow gaps in 31% of the cases, with 90% of these occurring in the nondominant transverse sinus and 10% in the codominant transverse sinuses. No flow gaps occurred in the dominant transverse sinuses. The superior sagittal and straight sinuses were seen in every venogram; the occipital sinus was seen in only 10%. The vein of Galen and internal cerebral veins were also seen in every case; the basal veins of Rosenthal were present in 91%. CONCLUSIONS: Transverse sinus flow gaps can be observed in as many as 31% of patients with normal MR imaging findings; these gaps should not be mistaken for dural sinus thrombosis.

MR angiography. Toward faster and more accurate methods.

MR angiography is a class of methods developed to noninvasively evaluate vascular structures. After first reviewing the different approaches and comparing strengths and weaknesses, new methods to improve the quality or speed of acquisition of these important sequences are examined.

The radiographic and imaging characteristics of porous tantalum implants within the human cervical spine.

STUDY DESIGN: Seven cadaveric cervical spines were implanted with a porous tantalum spacer and a titanium alloy spacer, and their radiographic and imaging characteristics were evaluated. OBJECTIVE: To determine the radiographic characteristics of porous tantalum and titanium implants used as spacers in the cervical spine. SUMMARY OF BACKGROUND DATA: Anterior decompressive surgery of the disc space or the vertebral body creates a defect that frequently is repaired with autologous bone grafts to promote spinal fusion. Donor site morbidity, insufficient donor material, and additional surgical time have spurred the development of biomaterials to replace or supplement existing spinal reconstruction techniques. Although the promotion of a solid bony fusion is critical, the implanted biomaterial should be compatible with modern imaging techniques, should allow visualization of the spinal canal and neural foramina, and should permit radiographic assessment of bony ingrowth. METHODS: Cadaveric spines containing the implants were imaged with plain radiography, computerized tomography, and magnetic resonance imaging. The image distortion produced by the implants was determined qualitatively and quantitatively. RESULTS: The tantalum and titanium spacers were opaque on plain radiographic films. On computed tomographic scans, more streak artifact was associated with the tantalum implants than with the titanium. On magnetic resonance imaging, the porous tantalum implant demonstrated less artifact than did the titanium spacer on T1- and T2-weighted spin echo and on T2*-weighted gradient-echo magnetic resonance images. Overall, the tantalum implant produced less artifact on magnetic resonance imaging than did the titanium spacer and therefore allowed for better visualization of the surrounding bony and neural structures. CONCLUSION: The material properties of titanium and porous tantalum cervical interbody implants contribute to their differential appearance in different imaging methods. The titanium implant appears to image best with computed tomography, whereas the porous tantalum implant produces less artifact than does the titanium implant on several magnetic resonance imaging sequences.

Differentiating recurrent tumor from radiation necrosis: time for re-evaluation of positron emission tomography?

UNLABELLED: Our purpose was to evaluate the ability of FDG PET to differentiate recurrent tumor from posttherapy radiation necrosis. METHODS: MR images, PET scans, and medical records of 84 consecutive patients with a history of a treated intracranial neoplasm were evaluated retrospectively. In all patients, recurrent tumor or radiation necrosis was suggested by clinical or MR findings. Metabolic activity of the PET abnormality was compared qualitatively with normal contralateral gray and white matter. RESULTS: PET findings were confirmed histologically in 31 patients. With contralateral white matter as the standard of comparison, the PET scan sensitivity and specificity were found to be 86% and 22%, respectively. With contralateral gray matter as the reference standard, the sensitivity and specificity became 73% and 56%, respectively. Overall, nearly one third of the patients would have been treated inappropriately in either scheme had the PET scan been the sole determinant of therapy. CONCLUSION: Our data suggest that the ability of FDG PET to differentiate recurrent tumor from radiation necrosis is limited. Both false-positive and false-negative PET scan results contributed to unacceptably low sensitivity and specificity values.

Absence of pontine lesions in narcolepsy.

A recent study reporting pontine lesions on magnetic resonance imaging in three patients with idiopathic narcolepsy postulated that the lesions represented tissue change secondary to long duration of disease. We studied twelve narcoleptic patients with MRI to validate these findings. The diagnosis of narcolepsy was established with both clinical and electrophysiological criteria in all twelve patients. Pontine lesions were present in two patients, both of whom were hypertensive. The lesions were associated with similar lesions in the hemispheres and were indistinguishable from ischemic change. No lesions were evident in the other ten patients, eight of whom were normotensive, and six of whom had narcolepsy for more than 37 years. We were unable to confirm the presence of pontine lesions specific to narcolepsy.