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.

Retinal Dystrophy Associated With RLBP1 Retinitis Pigmentosa: A Five-Year Prospective Natural History Study.

Purpose: To assess the progression in functional and structural measures over a five-year period in patients with retinal dystrophy caused by RLBP1 gene mutation. Methods: This prospective, noninterventional study included patients with biallelic RLBP1 mutations from two clinical sites in Sweden and Canada. Key assessments included ocular examinations, visual functional measures (best-corrected visual acuity [BCVA], contrast sensitivity [CS], dark-adaptation [DA] kinetics up to six hours for two wavelengths [450 and 632 nm], Humphrey visual fields [HVF], full-field flicker electroretinograms), and structural ocular assessments. Results: Of the 45 patients enrolled, 38 completed the full five years of follow-up. At baseline, patients had BCVA ranging from -0.2 to 1.3 logMAR, poor CS, HVF defects, and prominent thinning in central foveal thickness. All patients had extremely prolonged DA rod recovery of approximately six hours at both wavelengths. The test-retest repeatability was high across all anatomic and functional endpoints. Cross-sectionally, poorer VA was associated with older age (right eye, correlation coefficient [CC]: 0.606; left eye, CC: -0.578; P < 0.001) and HVF MD values decreased with age (right eye, CC: -0.672, left eye, CC: -0.654; P < 0.001). However, no major changes in functional or structural measures were noted longitudinally over the five-year period. Conclusions: This natural history study, which is the first study to monitor patients with RLBP1 RD for five years, showed that severely delayed DA sensitivity recovery, a characteristic feature of this disease, was observed in all patients across all age groups (17-69 years), making it a potentially suitable efficacy assessment for gene therapy treatment in this patient population.

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.

Topical Ocular TRPV1 Antagonist SAF312 (Libvatrep) Demonstrates Safety, Low Systemic Exposure, and No Anesthetic Effect in Healthy Participants.

Purpose: This first-in-human (FIH) study evaluated the safety, tolerability, pharmacokinetics, and effect on corneal sensitivity of topical ocular SAF312 in healthy participants. Methods: This double-masked, randomized study comprised single-ascending dose (SAD), multiple-ascending dose (MAD), and esthesiometry parts. In SAD and MAD, 8 participants in each dose cohort were randomized 3:1 to receive SAF312 or vehicle, 1 drop once (SAD), or 1 drop 4 or 8 times daily for 7 days (MAD). Safety and pharmacokinetics were the primary and secondary objectives. Blink rate, tear production, tear film break-up time (TFBUT), and corneal sensitivity were also explored. Results: SAF312 was tolerated in single and multiple doses, including the maximum concentration of 2.5% dosed up to 1 drop 8 times daily for 7 days. Most adverse events (AEs) were mild and similar between SAF312 and vehicle-treated groups. No serious AEs were reported. SAF312 was rapidly absorbed, and had low systemic exposure. After supratherapeutic dosing for 7 days, mean steady-state exposures of SAF312 were low and afforded safety margins of >70-fold compared with no-observed-AE levels following oral dosing in preclinical studies. No clinically relevant changes were observed in blink rate, tear production, and TFBUT. SAF312 showed no undesired anesthetic effect on the cornea. Conclusions: SAF312 was well tolerated, with no ocular or systemic safety concerns; had no anesthetic effect, and demonstrated rapid topical absorption with low systemic exposure. Translational Relevance: This work bridges the gap between basic research and clinical care by providing FIH data of SAF312, supporting the further investigation as a potential treatment for ocular surface pain.

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.

Structural and mechanical parameters of trabecular bone estimated from in vivo high-resolution magnetic resonance images at 3 tesla field strength.

PURPOSE: To evaluate the performance of a new 3 Tesla (T) high-resolution trabecular bone (TB) imaging technique at two resolution regimens in terms of serial reproducibility and sensitivity. MATERIALS AND METHODS: The left distal tibial metaphysis of seven healthy volunteers was imaged at three time-points using a FLASE (fast large-angle spin-echo) pulse sequence at 137 x 137 x 410 mum(3) and (160 mum)(3) voxel sizes. Image artifacts, motion degradation, and serial image volume misalignments were controlled to maximize reproducibility of image-derived measures of scale, topology, orientation in terms of structural anisotropy, and finite-element derived Young's and shear moduli. Coefficients of variation (CV) and intraclass correlation coefficients (ICC) for structural and mechanical parameters were evaluated as measures of reproducibility and reliability. The ability of structural and mechanical parameters to distinguish between subjects was tested by analysis of variance. RESULTS: Reproducibility was generally higher in the anisotropic data (CVs 1-5% versus 1-9% for isotropic images). Anisotropic voxel size yielded greater measurement reliability (ICCs 0.75-0.99, mean = 0.92 versus 0.62-0.99, mean = 0.86) and better discrimination of the seven subjects (75% versus 50% of the possible comparisons were significantly different [P < 0.05]) except for measures of structural anisotropy and topology. Isotropic resolution improved detection of structural orientation and permitted visualization of small perforations in longitudinal trabecular plates not detected at anisotropic resolution. CONCLUSION: Improved image acquisition and processing techniques enhance reproducibility of structural and mechanical parameters derived from high-resolution MRI of metaphyseal bone in the distal tibia.

Trabecular structure quantified with the MRI-based virtual bone biopsy in postmenopausal women contributes to vertebral deformity burden independent of areal vertebral BMD.

UNLABELLED: In postmenopausal women with a wide range of vertebral deformities, MRI-based structural measures of topology and scale at the distal radius are shown to account for as much as 30% of vertebral deformity, independent of integral vertebral BMD. INTRODUCTION: Trabecular bone architecture has been postulated to contribute to overall bone strength independent of vertebral BMD measured by DXA. However, there has thus far been only sparse in vivo evidence to support this hypothesis. MATERIALS AND METHODS: Postmenopausal women, 60-80 yr of age, were screened by DXA, and those with T-scores at either the hip or spine falling within the range of -2.5 +/- 1.0 were studied with the MRI-based virtual bone biopsy, along with heel broadband ultrasound absorption and pQCT of the tibia. The data from 98 subjects meeting the enrollment criteria were subjected to microMRI at the distal tibia and radius, and measures of topology and scale of the trabecular bone network were computed. A spinal deformity index (SDI) was obtained from morphometric measurements in midline sagittal MR images of the thoracic and lumbar spine to evaluate associations between structure and deformity burden. RESULTS: A number of structural indices obtained at the distal radius were correlated with the SDI. Among these were the topological surface density (a measure of trabecular plates) and trabecular bone volume fraction, which were inversely correlated with SDI (p < 0.0001). Combinations of two structural parameters accounted for up to 30% of the variation in SDI (p < 0.0001) independent of spinal BMD, which was not significantly correlated. pQCT trabecular BMD was also weakly associated, whereas broadband ultrasound absorption was not. No significant association between SDI and structural indices were found at the tibia. CONCLUSIONS: Structural measures at the distal radius obtained in vivo by microMRI explained a significant portion of the variation in total spinal deformity burden in postmenopausal women independent of areal BMD.

A Randomized, Controlled Phase I/II Study to Evaluate the Safety and Efficacy of MGV354 for Ocular Hypertension or Glaucoma.

PURPOSE: To assess the clinical safety, tolerability, and efficacy of topically administered MGV354, a soluble guanylate cyclase (sGC) activator, in patients with ocular hypertension (OH) or glaucoma. DESIGN: Double-masked, randomized, and vehicle-controlled study. METHODS: Parts 1 and 2 evaluated safety and tolerability to identify the maximum tolerated dose (MTD) of once-daily MGV354 in 32 healthy volunteers (Part 1) and 16 patients with OH or glaucoma (Part 2) at a single clinical site. Part 3 was a multisite trial that evaluated intraocular pressure (IOP)-lowering efficacy of the MTD administered nightly for 1 week in 50 patients with minimum IOP of 24 mm Hg at 8 AM, with a main outcome measure of mean diurnal IOP at day 8 compared to baseline (ClinicalTrials.govNCT02743780). RESULTS: There was no difference in favor of MGV354 for IOP lowering; change from baseline to day 8 in mean diurnal IOP was -0.6 mm Hg for MGV354-treated patients and -1.1 mm Hg for vehicle-treated patients in Part 3, with a confidence interval of -0.7 to 1.7. The most common adverse events reported after MGV354 administration were conjunctival and ocular hyperemia. CONCLUSIONS: Overall, MGV354 0.1% demonstrated no statistically significant effect compared to vehicle in lowering IOP based on the study's main outcome measure. MGV354 produced ocular hyperemia consistent with its pharmacology.

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.

Helping America's most vulnerable children and parents.

This article focuses on ways the government should allocate resources in order to support America's most vulnerable children and parents. Government policies on helping children seek to achieve many outcomes, but four are especially important: (a) protecting children's basic physical safety and mental safety (i.e., sense of emotional security in relationships with one's parents) during childhood; (b) ensuring that children do not suffer from serious mental health problems that impair their adjustment and ability to function well at home, at school, and in social relations; (c) helping all children acquire the academic skills needed for economic "success" (i.e., having the capacity to earn a "middle class" income); and (d) increasing equal opportunity for economic and social mobility. In trying to achieve these four outcomes, policymakers must decide how to allocate resources among programs that focus primarily on the child, such as preschool and K-12 education; programs seeking to improve parenting, such as home visiting; and programs that provide economic resources, such as cash and subsidies, to families. This article elaborates on this approach. (PsycINFO Database Record

Effect of testosterone replacement on trabecular architecture in hypogonadal men.

UNLABELLED: We evaluated the effect of testosterone treatment on trabecular architecture by microMRI in 10 untreated severely hypogonadal men. After 2 years, microMRI parameters of trabecular connectivity improved significantly, suggesting the possibility that testosterone improves trabecular architecture. INTRODUCTION: Osteoporosis, characterized by low BMD and diminished bone quality, is a significant public health problem in men. Hypogonadal men have decreased BMD and deteriorated trabecular architecture compared with eugonadal men, and testosterone treatment improves their BMD. We tested the hypothesis that testosterone replacement in hypogonadal men would also improve their trabecular architecture. MATERIALS AND METHODS: We selected 10 untreated severely hypogonadal men and treated them with a testosterone gel for 24 months to maintain their serum testosterone concentrations within the normal range. Each subject was assessed before and after 6, 12, and 24 months of testosterone treatment by magnetic resonance microimaging (microMRI) of the distal tibia and by DXA of the spine and hip. The microMRI parameters reflect the integrity of the trabecular network and include the ratio of all surface voxels (representing plates) to curve voxels (representing rods) and the topological erosion index, a ratio of topological parameters expected to increase on trabecular deterioration to those expected to decrease. The higher the surface-to-curve ratio and the lower the topological erosion index, the more intact the trabecular network. RESULTS: Serum testosterone concentrations increased to midnormal after 3 months of treatment and remained normal thereafter. After 24 months of testosterone treatment, BMD of the spine increased 7.4% (p<0.001), and of the total hip increased 3.8% (p=0.008). Architectural parameters assessed by microMRI also changed: the surface-to-curve ratio increased 11% (p=0.004) and the topological erosion index decreased 7.5% (p=0.004). CONCLUSIONS: These results suggest the possibility that testosterone replacement of hypogonadal men improves trabecular architecture.

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.