Cerebral Edema in Patients With Large Hemispheric Infarct Undergoing Reperfusion Treatment: A HERMES Meta-Analysis.

Background and Purpose: Whether reperfusion into infarcted tissue exacerbates cerebral edema has treatment implications in patients presenting with extensive irreversible injury. We investigated the effects of endovascular thrombectomy and reperfusion on cerebral edema in patients presenting with radiological evidence of large hemispheric infarction at baseline. Methods: In a systematic review and individual patient-level meta-analysis of 7 randomized controlled trials comparing thrombectomy versus medical therapy in anterior circulation ischemic stroke published between January 1, 2010, and May 31, 2017 (Highly Effective Reperfusion Using Multiple Endovascular Devices collaboration), we analyzed the association between thrombectomy and reperfusion with maximal midline shift (MLS) on follow-up imaging as a measure of the space-occupying effect of cerebral edema in patients with large hemispheric infarction on pretreatment imaging, defined as diffusion-magnetic resonance imaging or computed tomography (CT)-perfusion ischemic core 80 to 300 mL or noncontrast CT-Alberta Stroke Program Early CT Score ≤5. Risk of bias was assessed using the Cochrane tool. Results: Among 1764 patients, 177 presented with large hemispheric infarction. Thrombectomy and reperfusion were associated with functional improvement (thrombectomy common odds ratio =2.30 [95% CI, 1.32­4.00]; reperfusion common odds ratio =4.73 [95% CI, 1.66­13.52]) but not MLS (thrombectomy ß=−0.27 [95% CI, −1.52 to 0.98]; reperfusion ß=−0.78 [95% CI, −3.07 to 1.50]) when adjusting for age, National Institutes of Health Stroke Score, glucose, and time-to-follow-up imaging. In an exploratory analysis of patients presenting with core volume >130 mL or CT-Alberta Stroke Program Early CT Score ≤3 (n=76), thrombectomy was associated with greater MLS after adjusting for age and National Institutes of Health Stroke Score (ß=2.76 [95% CI, 0.33­5.20]) but not functional improvement (odds ratio, 1.71 [95% CI, 0.24­12.08]). Conclusions: In patients presenting with large hemispheric infarction, thrombectomy and reperfusion were not associated with MLS, except in the subgroup with very large core volume (>130 mL) in whom thrombectomy was associated with increased MLS due to space-occupying ischemic edema. Mitigating cerebral edema-mediated secondary injury in patients with very large infarcts may further improve outcomes after reperfusion therapies.

Automated Calculation of Alberta Stroke Program Early CT Score: Validation in Patients With Large Hemispheric Infarct.

Background and Purpose- We compared the Alberta Stroke Program Early CT Score (ASPECTS), calculated using a machine learning-based automatic software tool, RAPID ASPECTS, as well as the median score from 4 experienced readers, with the diffusion-weighted imaging (DWI) ASPECTS obtained following the baseline computed tomography (CT) in patients with large hemispheric infarcts. Methods- CT and magnetic resonance imaging scans from the GAMES-RP study, which enrolled patients with large hemispheric infarctions (82-300 mL) documented on DWI-magnetic resonance imaging, were evaluated by blinded experienced readers to determine both CT and DWI ASPECTS. The CT scans were also evaluated by an automated software program (RAPID ASPECTS). Using the DWI ASPECTS as a reference standard, the median CT ASPECTS of the clinicians and the automated score were compared using the interclass correlation coefficient. Results- The median CT ASPECTS for the clinicians was 5 (interquartile range, 4-7), for RAPID ASPECTS 3 (interquartile range, 1-6), and for DWI ASPECTS 3 (2-4). Median error for RAPID ASPECTS was 1 (interquartile range, -1 to 3) versus 3 (interquartile range, 1-4) for clinicians (P<0.001). The automated score had a higher level of agreement with the median of the DWI ASPECTS, both for the full scale and when dichotomized at <6 versus 6 or more (difference in intraclass correlation coefficient, P=0.001). Conclusions- RAPID ASPECTS was more accurate than experienced clinicians in identifying early evidence of brain ischemia as documented by DWI.

Pharmacological modulation of brain activity in a preclinical model of osteoarthritis.

The earliest stages of osteoarthritis are characterized by peripheral pathology; however, during disease progression chronic pain emerges-a major symptom of osteoarthritis linked to neuroplasticity. Recent clinical imaging studies involving chronic pain patients, including osteoarthritis patients, have demonstrated that functional properties of the brain are altered, and these functional changes are correlated with subjective behavioral pain measures. Currently, preclinical osteoarthritis studies have not assessed if functional properties of supraspinal pain circuitry are altered, and if these functional properties can be modulated by pharmacological therapy either by direct or indirect action on brain systems. In the current study, functional connectivity was first assessed in order to characterize the functional neuroplasticity occurring in the rodent medial meniscus tear (MMT) model of osteoarthritis-a surgical model of osteoarthritis possessing peripheral joint trauma and a hypersensitive pain state. In addition to knee joint trauma at week 3 post-MMT surgery, we observed that supraspinal networks have increased functional connectivity relative to sham animals. Importantly, we observed that early and sustained treatment with a novel, peripherally acting broad-spectrum matrix metalloproteinase (MMP) inhibitor (MMPi) significantly attenuates knee joint trauma (cartilage degradation) as well as supraspinal functional connectivity increases in MMT animals. At week 5 post-MMT surgery, the acute pharmacodynamic effects of celecoxib (selective cyclooxygenase-2 inhibitor) on brain function were evaluated using pharmacological magnetic resonance imaging (phMRI) and functional connectivity analysis. Celecoxib was chosen as a comparator, given its clinical efficacy for alleviating pain in osteoarthritis patients and its peripheral and central pharmacological action. Relative to the vehicle condition, acute celecoxib treatment in MMT animals yielded decreased phMRI infusion responses and decreased functional connectivity, the latter observation being similar to what was detected following chronic MMPi treatment. These findings demonstrate that an assessment of brain function may provide an objective means by which to further evaluate the pathology of an osteoarthritis state as well as measure the pharmacodynamic effects of therapies with peripheral or peripheral and central pharmacological action.

Predicting trabecular bone elastic properties from measures of bone volume fraction and fabric on the basis of micromagnetic resonance images.

The relationship between fabric (a measure of structural anisotropy) and elastic properties of trabecular bone was examined by invoking morphology and homogenization theory on the basis of micromagnetic resonance images from the distal tibia in specimens (N = 30) and human subjects (N = 16) acquired at a 160 × 160 × 160 µm(3) voxel size. The fabric tensor was mapped in 7.5 × 7.5 × 7.5 mm(3) cubic subvolumes by a three-dimensional mean-intercept-length method. Elastic constants (three Young's and three shear moduli) were derived from linear microfinite element simulations of three-dimensional grayscale bone volume fraction-mapped images. In the specimen data, moduli fit power laws of bone volume fraction (bone volume/total volume) for all three test directions and subvolumes (R(2) = 0.92-0.98) with exponents ranging from 1.3 to 1.8. Weaker linear relationships were found for the in vivo data because of a narrower range in bone volume/total volume. When pooling the data for all test directions and subvolumes, bone volume/total volume predicted elastic moduli less well in the specimens (mean R(2) = 0.74) and not at all in vivo. A model of bone volume/total volume and fabric was highly predictive of microfinite element-derived Young's moduli: mean R(2) s of 0.98 and 0.82 (in vivo). The results show that fabric, an important predictor of bone mechanical properties, can be assessed in the limited resolution and signal-to-noise ratio regime of micromagnetic resonance images.

Performance of µMRI-Based virtual bone biopsy for structural and mechanical analysis at the distal tibia at 7T field strength.

PURPOSE: To assess the performance of a 3D fast spin echo (FSE) pulse sequence utilizing out-of-slab cancellation through phase alternation and micro-magnetic resonance imaging (µMRI)-based virtual bone biopsy processing methods to probe the serial reproducibility and sensitivity of structural and mechanical parameters of the distal tibia at 7.0T. MATERIALS AND METHODS: The distal tibia of five healthy subjects was imaged at three timepoints with a 3D FSE sequence at 137 × 137 × 410 µm(3) voxel size. Follow-up images were retrospectively 3D registered to baseline images. Coefficients of variation (CV) and intraclass correlation coefficients (ICCs) for measures of scale and topology of the whole tibial trabecular bone (TB) cross-section as well as finite-element-derived Young's and shear moduli of central cuboidal TB subvolumes (8 × 8 × 5 mm(3) ) were evaluated as measures of reproducibility and reliability. Four additional cubic TB subregions (anterior, medial, lateral, and posterior) of similar dimensions were extracted and analyzed to determine associations between whole cross-section and subregional structural parameters. RESULTS: The mean signal-to-noise ratio (SNR) over the 15 image acquisitions was 27.5 ± 2.1. Retrospective registration yielded an average common analysis volume of 67% across the three exams per subject. Reproducibility (mean CV = 3.6%; range, 1.5%-5%) and reliability (ICCs, 0.95-0.99) of all parameters permitted parameter-based discrimination of the five subjects in spite of the narrow age range (26-36 years) covered. Parameters characterizing topology were better able to distinguish two individuals who demonstrated similar values for scalar measurements (≈ 34% difference, P < 0.001). Whole-section axial stiffness encompassing the cortex was superior at distinguishing two individuals relative to its central subregional TB counterpart (≈ 8% difference; P < 0.05). Interregion comparisons showed that although all parameters were correlated (mean R(2) = 0.78; range 0.57-0.99), the strongest associations observed were those for the erosion index (mean R(2) = 0.95, P ≤ 0.01). CONCLUSION: The reproducibility and structural and mechanical parameter-based discriminative ability achieved in five healthy subjects suggests that 7T-derived µMRI of TB can be applied towards serial patient studies of osteoporosis and may enable earlier detection of disease or treatment-based effects.

Safety and efficacy of anti-tau monoclonal antibody gosuranemab in progressive supranuclear palsy: a phase 2, randomized, placebo-controlled trial.

A randomized, double-blind, placebo-controlled, 52-week study (no. NCT03068468) evaluated gosuranemab, an anti-tau monoclonal antibody, in the treatment of progressive supranuclear palsy (PSP). In total, 486 participants dosed were assigned to either gosuranemab (n = 321) or placebo (n = 165). Efficacy was not demonstrated on adjusted mean change of PSP Rating Scale score at week 52 between gosuranemab and placebo (10.4 versus 10.6, P = 0.85, primary endpoint), or at secondary endpoints, resulting in discontinuation of the open-label, long-term extension. Unbound N-terminal tau in cerebrospinal fluid decreased by 98% with gosuranemab and increased by 11% with placebo (P < 0.0001). Incidences of adverse events and deaths were similar between groups. This well-powered study suggests that N-terminal tau neutralization does not translate into clinical efficacy.

Spatial autocorrelation and mean intercept length analysis of trabecular bone anisotropy applied to in vivo magnetic resonance imaging.

Osteoporosis is characterized by bone loss and deterioration of the trabecular bone (TB) architecture that leads to impaired overall mechanical strength of the bone. Bone mineral density (BMD) measured by dual-energy x-ray absorptiometry is currently the standard clinical metric assessing bone integrity but it fails to capture the structural changes in the TB. Recent research suggests that structure contributes to bone strength in a manner complementary to BMD. Besides parameters of scale such as the mean TB thickness and mean bone volume fraction, parameters describing the anisotropy of the trabecular architecture play an important role in the characterization of TB since trabeculae are preferentially oriented along the direction of local loading. Therefore, the degree of structural anisotropy is of pivotal importance to the bone's mechanical competence. The most common method for measuring structural anisotropy of TB is the mean-intercept length (MIL). In this work we present a method, based on the three-dimensional spatial autocorrelation function (ACF), for mapping of the full structural anisotropy ellipsoid of both TB thickness and spacing and we examine its performance as compared to that of MIL. Not only is the ACF method faster by several orders of magnitude, it is also considerably more robust to noise. Further, it is applicable at lower spatial resolution and is relatively insensitive to image shading. The chief reason for ACF's superior performance is that it does not require binarization, which is difficult to achieve in the limited spatial regime of in vivo magnetic resonance imaging. MIL and ACF have been applied to high-resolution magnetic resonances images of the tibia in a group of ten healthy postmenopausal women by comparing the structural anisotropy and principal direction of the computed fabric tensor for each method. While there is fair agreement between the two methods, ACF analysis yielded greater anisotropy than MIL for both TB thickness and spacing. There was good agreement between the two techniques as far as the eigenvectors of the fabric ellipsoids were concerned, which parallel the bone's macroscopic axis.

Effect of parathyroid hormone combined with gait training on bone density and bone architecture in people with chronic spinal cord injury.

OBJECTIVE: To evaluate the response of bone to 2 anabolic stimuli, teriparatide and mechanical loading, in subjects with spinal cord injury. DESIGN: A pilot study, 1 group, pretest-posttest. SETTING: A rehabilitation hospital. PARTICIPANTS: A convenience sample of 12 nonambulatory chronic spinal cord injury subjects. METHODS: The subjects were administered open-label teriparatide 20 µg/d while undergoing robotic-assisted stepping 3 times a week for 6 months, followed by 6 months of teriparatide alone. MAIN OUTCOME MEASUREMENTS: Bone status was evaluated at 3, 6, and 12 months by using dual-energy x-ray absorptiometry to calculate bone mineral density (BMD) at the spine and hip, magnetic resonance imaging to assess bone microarchitecture of the distal tibia, and serum bone markers. RESULTS: Mean (SD) baseline BMD measurements at the spine and the left and right total hip were 1.05 ± 0.162 g/cm(2), 0.638 ± 0.090 g/cm(2) and 0.626 ± 0.088 g/cm(2), respectively. After 6 months of treatment, BMD changed 2.19% ± 3.61%, 0.02% ± 2.21%, and 0.74% ± 2.80% at the spine, and left and right total hip, respectively. These changes were not statistically significant (P > .05 for all). Magnetic resonance imaging supported an anabolic effect after 3 months of treatment with significant (P < .05) changes in trabecular thickness, 4.4% ± 4.06%; surface-to-curve ratio, 23.6% ± 22.3%; and erosion index, -17.04% ± 12.9%. Although the trend remained after 6 months, statistical significance was not retained. At 6 months, bone markers indicated an increase in mean levels of bone-specific alkaline phosphatase, 53.8% ± 62.9%; C-terminal telopeptides of type I collagen, 137.6% ± 194.6%; and intact amino-terminal propeptide of type I procollagen, 61.4% ± 99.3%. CONCLUSION: In this limited pilot study, teriparatide and mechanical loading resulted in a numerical but not statistically significant increase in lumbar spine BMD and no significant BMD changes at the hip. Magnetic resonance imaging at the distal tibia suggested an anabolic effect, but the high sensitivity offered by this technique was challenged by the limited ability to obtain analyzable data from all the subjects. Further studies that involve longer treatment periods and greater mechanical loading are warranted.

Performance of the MRI-based virtual bone biopsy in the distal radius: serial reproducibility and reliability of structural and mechanical parameters in women representative of osteoporosis study populations.

Serial reproducibility and reliability critically determine sensitivity to detect changes in response to intervention and provide a basis for sample size estimates. Here, we evaluated the performance of the MRI-based virtual bone biopsy in terms of 26 structural and mechanical parameters in the distal radius of 20 women in the age range of 50 to 75 years (mean=62.0 years, S.D.=8.1 years), representative of typical study populations in drug intervention trials and fracture studies. Subjects were examined three times at average intervals of 20.2 days (S.D.=14.5 days) by MRI at 1.5 T field strength at a voxel size of 137×137×410 µm(3). Methods involved prospective and retrospective 3D image registration and auto-focus motion correction. Analyses were performed from a central 5×5×5 mm(3) cuboid subvolume and trabecular volume consisting of a 13 mm axial slab encompassing the entire medullary cavity. Whole-volume axial stiffness and sub-regional Young's and shear moduli were computed by finite-element analysis. Whole-volume-derived aggregate mean coefficient of variation of all structural parameters was 4.4% (range 1.8% to 7.7%) and 4.0% for axial stiffness; corresponding data in the subvolume were 6.5% (range 1.6% to 13.0%) for structural, and 5.5% (range 4.6% to 6.5%) for mechanical parameters. Aggregate ICC was 0.976 (range 0.947 to 0.986) and 0.992 for whole-volume-derived structural parameters and axial stiffness, and 0.946 (range 0.752 to 0.991) and 0.974 (range 0.965 to 0.978) for subvolume-derived structural and mechanical parameters, respectively. The strongest predictors of whole-volume axial stiffness were BV/TV, junction density, skeleton density and Tb.N (R(2) 0.79-0.87). The same parameters were also highly predictive of sub-regional axial modulus (R(2) 0.88-0.91). The data suggest that the method is suited for longitudinal assessment of the response to therapy. The underlying technology is portable and should be compatible with all general-purpose MRI scanners, which is appealing considering the very large installed base of this modality.

On the significance of motion degradation in high-resolution 3D µMRI of trabecular bone.

RATIONALE AND OBJECTIVES: Subtle subject movement during high-resolution three-dimensional micro-magnetic resonance imaging of trabecular bone (TB) causes blurring, thereby rendering the data unreliable for quantitative analysis. In this work, the effects of translational and rotational motion displacements were evaluated qualitatively and quantitatively. MATERIALS AND METHODS: In experiment 1, motion was induced by applying various simulated and previously observed in vivo trajectories as phase shifts to k-space or rotation angles to k-space segments of a virtually motion-free data set. In experiment 2, images that were visually free of motion artifacts from two groups of 10 healthy individuals, differing in age, were selected to probe the effects of motion on TB parameters. In both experiments, images were rated for motion severity, and the scores were compared to a focus criterion, the normalized gradient squared. RESULTS: Strong correlations were observed between the motion quality scores and the corresponding normalized gradient squared values (R(2) = 0.52-0.64, P < .01). The results from experiment 1 demonstrated consistently lower image quality and alterations in structural parameters of 9% to 45% with increased amplitude of displacements. In experiment 2, the significant differences in structural parameter group means of the motion-free images were lost upon motion degradation. Autofocusing, a postprocessing correction method, partially recovered the sharpness of the original motion-free images in 13 of 20 subjects. CONCLUSIONS: Quantitative TB structural measures are highly sensitive to subtle motion-induced degradation, which adversely affects precision and statistical power. The results underscore the influence of subject movement in high-resolution three-dimensional micro-magnetic resonance imaging and its correction for TB structure analysis.

Reduced bone mineral density is not associated with significantly reduced bone quality in men and women practicing long-term calorie restriction with adequate nutrition.

Calorie restriction (CR) reduces bone quantity but not bone quality in rodents. Nothing is known regarding the long-term effects of CR with adequate intake of vitamin and minerals on bone quantity and quality in middle-aged lean individuals. In this study, we evaluated body composition, bone mineral density (BMD), and serum markers of bone turnover and inflammation in 32 volunteers who had been eating a CR diet (approximately 35% less calories than controls) for an average of 6.8 ± 5.2 years (mean age 52.7 ± 10.3 years) and 32 age- and sex-matched sedentary controls eating Western diets (WD). In a subgroup of 10 CR and 10 WD volunteers, we also measured trabecular bone (TB) microarchitecture of the distal radius using high-resolution magnetic resonance imaging. We found that the CR volunteers had significantly lower body mass index than the WD volunteers (18.9 ± 1.2 vs. 26.5 ± 2.2 kg m(-2) ; P = 0.0001). BMD of the lumbar spine (0.870 ± 0.11 vs. 1.138 ± 0.12 g cm(-2) , P = 0.0001) and hip (0.806 ± 0.12 vs. 1.047 ± 0.12 g cm(-2) , P = 0.0001) was also lower in the CR than in the WD group. Serum C-terminal telopeptide and bone-specific alkaline phosphatase concentration were similar between groups, while serum C-reactive protein (0.19 ± 0.26 vs. 1.46 ± 1.56 mg L(-1) , P = 0.0001) was lower in the CR group. Trabecular bone microarchitecture parameters such as the erosion index (0.916 ± 0.087 vs. 0.877 ± 0.088; P = 0.739) and surface-to-curve ratio (10.3 ± 1.4 vs. 12.1 ± 2.1, P = 0.440) were not significantly different between groups. These findings suggest that markedly reduced BMD is not associated with significantly reduced bone quality in middle-aged men and women practicing long-term calorie restriction with adequate nutrition.

Computational biomechanics of the distal tibia from high-resolution MR and micro-CT images.

The mechanical properties of bone estimated by micro-finite element (microFE) analysis on the basis of in vivo micro-MR images (microMRIs) of the distal extremities provide a new tool for direct assessment of the mechanical consequences of intervention. However, the accuracy of the method has not previously been investigated. Here, we compared microFE-derived mechanical parameters obtained from microMRIs at 160 microm isotropic voxel size now achievable in vivo with those derived from 25 microm isotropic (reference) microCT images of 30 cadaveric tibiae from 15 donors (4 females and 11 males, aged 55-84 years). Elastic and shear moduli estimated from 5mm(3) subvolumes of trabecular bone (TB) derived from microMRIs were significantly correlated with those derived from volume-matched reference microCT images (R(2)=0.60-0.67). Axial stiffness of whole-bone sections (including both cortical and trabecular compartments) derived from microMR-based models were highly correlated (R(2)=0.85) with those from high-resolution reference images. Further, microFE models generated from microCT images after downsampling to lower resolutions relevant to in vivo microMRI (100-160 microm) showed mechanical parameters to be strongly correlated (R(2)>0.93) with those derived at reference resolution (25 microm). Incorporation of grayscale image information into the microMR-based microFE model yielded slopes closer to unity than binarized models (1.07+/-0.15 vs. 0.71+/-0.11) when correlated with reference subregional elastic and shear moduli. This work suggests that elastic properties of distal tibia can be reliably estimated by microFE analysis from microMRIs obtainable at in vivo resolution.

Accuracy of high-resolution in vivo micro magnetic resonance imaging for measurements of microstructural and mechanical properties of human distal tibial bone.

Micro magnetic resonance imaging (µMRI) is an in vivo imaging method that permits 3D quantification of cortical and trabecular bone microstructure. µMR images can also be used for building microstructural finite element (µFE) models to assess bone stiffness, which highly correlates with bone's resistance to fractures. In order for µMRI-based microstructural and µFE analyses to become standard clinical tools for assessing bone quality, validation with a current gold standard, namely, high-resolution micro computed tomography (µCT), is required. Microstructural measurements of 25 human cadaveric distal tibias were performed for the registered µMR and µCT images, respectively. Next, whole bone stiffness, trabecular bone stiffness, and elastic moduli of cubic subvolumes of trabecular bone in both µMR and µCT images were determined by voxel-based µFE analysis. The bone volume fraction (BV/TV), trabecular number (Tb.N*), trabecular spacing (Tb.Sp*), cortical thickness (Ct.Th), and structure model index (SMI) based on µMRI showed strong correlations with µCT measurements (r(2) = 0.67 to 0.97), and bone surface-to-volume ratio (BS/BV), connectivity density (Conn.D), and degree of anisotropy (DA) had significant but moderate correlations (r(2) = 0.33 to 0.51). Each of these measurements also contributed to one or many of the µFE-predicted mechanical properties. However, model-independent trabecular thickness (Tb.Th*) based on µMRI had no correlation with the µCT measurement and did not contribute to any mechanical measurement. Furthermore, the whole bone and trabecular bone stiffness based on µMRI were highly correlated with those of µCT images (r(2) = 0.86 and 0.96), suggesting that µMRI-based µFE analyses can directly and accurately quantify whole bone mechanical competence. In contrast, the elastic moduli of the µMRI trabecular bone subvolume had significant but only moderate correlations with their gold standards (r(2) = 0.40 to 0.58). We conclude that most microstructural and mechanical properties of the distal tibia can be derived efficiently from µMR images and can provide additional information regarding bone quality.